Tetrazolones as a Carboxylic Acid Bioisosteres

ABSTRACT

The present disclosure provides compounds that include a tetrazolone derivative of a carboxyl group of an active agent. This disclosure also relates to pharmaceutical compositions that include these compounds, methods of using these compounds in the treatment of various diseases and disorders, and processes for preparing these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority pursuant to 35 U.S.C. §119(e) to thefiling date of U.S. Provisional Application No. 62/107,948, filed Jan.26, 2015, the disclosure of which is herein incorporated by reference.

INTRODUCTION

Tetrazole is an organic heterocyclic compound that includes a 5-memberedring of four nitrogen atoms and one carbon atom (plus hydrogens), andhas the chemical formula CH₂N₄. A tetrazol-5-one group (also referred toas “tetrazolone”) includes an oxygen on the 5-position of the tetrazolering. When the nitrogen at the 4-position of tetrazolone isunsubstituted, the tetrazolone can have a similar pKa compared totetrazole, and can lower the calculated octanol-water partitioncoefficient (clog P). In addition, the presence of an oxygen on thetetrazolone ring can stabilize the localization of electron-density atthe nitrogen 4-position, allowing for 1,4-disubstituted analogs. Anexpedient synthesis of compounds containing the tetrazolone group may beused to produce compounds containing the tetrazolone group.

SUMMARY

The present disclosure provides compounds that include a tetrazolonederivative of a carboxyl group of an active agent. In some instances,the active agent is a biologically active agent, such as, but notlimited to, a pesticide, an herbicide or a therapeutically effectivecompound. This disclosure also relates to pharmaceutical compositionsthat include these compounds, methods of using these compounds in thetreatment of various diseases and disorders, and processes for preparingthese compounds.

In some embodiments, the tetrazolone derivative includes a tetrazoloneor a substituted tetrazolone. By “tetrazolone” is meant a tetrazol-5-onegroup.

Embodiments of chemical structures are provided throughout the presentdisclosure. By way of example, such compounds are represented by thefollowing formula:

wherein

R¹ is the active agent; and

R² is selected from hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl;

or a salt or stereoisomer thereof.

In some embodiments, R² is hydrogen or alkyl.

In some embodiments, the active agent is a therapeutically effectiveactive agent.

In some embodiments, the tetrazolone derivative is produced from thecarboxyl group of the active agent.

In some embodiments, the compound is selected from:

Aspects of the present disclosure include a pharmaceutical compositionthat includes a compound of the present disclosure and apharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition also includes asecond active agent.

Aspects of the present disclosure include a compound that includes atetrazolone or substituted tetrazolone produced from a carboxyl group ofan active agent.

Aspects of the present disclosure include a method of treating a diseaseor disorder in a subject in need of treatment, where the method includesadministering to the subject a compound of the present disclosure.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A shows a graph of agonist response (% control) vs. Logconcentration (M) for compound1-(4′-((1,7-dimethyl-2′-propyl-1H,3′H-[2,5′-dibenzo[d]imidazol]-3′-yl)methyl-[1,1′-biphenyl-2-yl)-1,4-dihydro-5H-tetrazol-5-one6t, according to embodiments of the present disclosure. FIG. 1B shows agraph of agonist response (% control) vs. Log concentration (M) forcompound4′-((1,7-dimethyl-2′-propyl-1H,3′H-[2,5′-dibenzo[d]imidazol]-3′-yl)methyl-[1,1′-biphenyl)-2-carboxylicacid (Telmisartan).

DETAILED DESCRIPTION

The present disclosure provides compounds that include a tetrazolonederivative of a carboxyl group of an active agent. In some instances,the active agent is a biologically active agent, such as, but notlimited to, a pesticide, an herbicide or a therapeutically effectivecompound. This disclosure also relates to pharmaceutical compositionsthat include these compounds, methods of using these compounds in thetreatment of various diseases and disorders, and processes for preparingthese compounds.

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

It is noted that as used herein and in the appended claims, the singularforms “a,” “an,” and “the” include plural referents unless the contextclearly dictates otherwise. It is further noted that the claims may bedrafted to exclude any optional element. As such, this statement isintended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is specifically contemplated. The upper and lower limitsof these smaller ranges may independently be included in the smallerranges, and are also encompassed within the invention, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the invention.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbookof Practical Organic Chemistry, Including Qualitative Organic Analysis,Fourth Edition, New York: Longman, 1978.

The nomenclature used herein to name the subject compounds isillustrated in the Examples herein. This nomenclature has generally beenderived using the commercially-available AutoNom software (MDL, SanLeandro, Calif.).

TERMS

The following terms have the following meanings unless otherwiseindicated. Any undefined terms have their art recognized meanings.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms.This term includes, by way of example, linear and branched hydrocarbylgroups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—),isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—),sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl(CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

The term “substituted alkyl” refers to an alkyl group as defined hereinwherein one or more carbon atoms in the alkyl chain have been optionallyreplaced with a heteroatom such as —O—, —N—, —S—, —S(O)_(n)— (where n is0 to 2), —NR— (where R is hydrogen or alkyl) and having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-aryl,—SO₂-heteroaryl, and —NR^(a)R^(b), wherein R′ and R″ may be the same ordifferent and are chosen from hydrogen, optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl andheterocyclic.

“Alkylene” refers to divalent aliphatic hydrocarbyl groups preferablyhaving from 1 to 6 and more preferably 1 to 3 carbon atoms that areeither straight-chained or branched, and which are optionallyinterrupted with one or more groups selected from —O—, —NR¹⁰—,—NR¹⁰C(O)—, —C(O)NR¹⁰— and the like. This term includes, by way ofexample, methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), iso-propylene (—CH₂CH(CH₃)—), (—C(CH₃)₂CH₂CH₂—),(—C(CH₃)₂CH₂C(O)—), (—C(CH₃)₂CH₂C(O)NH—), (—CH(CH₃)CH₂—), and the like.

“Substituted alkylene” refers to an alkylene group having from 1 to 3hydrogens replaced with substituents as described for carbons in thedefinition of “substituted” below.

The term “alkane” refers to alkyl group and alkylene group, as definedherein.

The term “alkylaminoalkyl”, “alkylaminoalkenyl” and “alkylaminoalkynyl”refers to the groups R′NHR″— where R′ is alkyl group as defined hereinand R″ is alkylene, alkenylene or alkynylene group as defined herein.

The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and-substituted alkylene-aryl where alkylene, substituted alkylene and arylare defined herein.

“Alkoxy” refers to the group —O-alkyl, wherein alkyl is as definedherein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. Theterm “alkoxy” also refers to the groups alkenyl-O—, cycloalkyl-O—,cycloalkenyl-O—, and alkynyl-O—, where alkenyl, cycloalkyl,cycloalkenyl, and alkynyl are as defined herein.

The term “substituted alkoxy” refers to the groups substituted alkyl-O—,substituted alkenyl-O—, substituted cycloalkyl-O—, substitutedcycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl,substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyland substituted alkynyl are as defined herein.

The term “alkoxyamino” refers to the group —NH-alkoxy, wherein alkoxy isdefined herein.

The term “haloalkoxy” refers to the groups alkyl-O— wherein one or morehydrogen atoms on the alkyl group have been substituted with a halogroup and include, by way of examples, groups such as trifluoromethoxy,and the like.

The term “haloalkyl” refers to a substituted alkyl group as describedabove, wherein one or more hydrogen atoms on the alkyl group have beensubstituted with a halo group. Examples of such groups include, withoutlimitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl,trifluoroethyl and the like.

The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl,alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, andsubstituted alkylene-O-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.

The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl,alkylene-S-substituted alkyl, substituted alkylene-S-alkyl andsubstituted alkylene-S-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.

“Alkenyl” refers to straight chain or branched hydrocarbyl groups havingfrom 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and havingat least 1 and preferably from 1 to 2 sites of double bond unsaturation.This term includes, by way of example, bi-vinyl, allyl, andbut-3-en-1-yl. Included within this term are the cis and trans isomersor mixtures of these isomers.

The term “substituted alkenyl” refers to an alkenyl group as definedherein having from 1 to 5 substituents, or from 1 to 3 substituents,selected from alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO— substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Alkynyl” refers to straight or branched monovalent hydrocarbyl groupshaving from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms andhaving at least 1 and preferably from 1 to 2 sites of triple bondunsaturation. Examples of such alkynyl groups include acetylenyl(—C≡CH), and propargyl (—CH₂C≡CH).

The term “substituted alkynyl” refers to an alkynyl group as definedherein having from 1 to 5 substituents, or from 1 to 3 substituents,selected from alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO— substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, and —SO₂-heteroaryl.

“Alkynyloxy” refers to the group —O-alkynyl, wherein alkynyl is asdefined herein. Alkynyloxy includes, by way of example, ethynyloxy,propynyloxy, and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclyl-C(O)—, and substitutedheterocyclyl-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein. For example, acylincludes the “acetyl” group CH₃C(O)—

“Acylamino” refers to the groups —NR²⁰C(O)alkyl, —NR²⁰C(O)substitutedalkyl, N R²⁰C(O)cycloalkyl, —NR²⁰C(O)substituted cycloalkyl,—NR²⁰C(O)cycloalkenyl, —NR²⁰C(O)substituted cycloalkenyl,—NR²⁰C(O)alkenyl, —NR²⁰C(O)substituted alkenyl, —NR²⁰C(O)alkynyl,—NR²⁰C(O)substituted alkynyl, —NR²⁰C(O)aryl, —NR²⁰C(O)substituted aryl,—NR²⁰C(O)heteroaryl, —NR²⁰C(O)substituted heteroaryl,—NR²⁰C(O)heterocyclic, and —NR²⁰C(O)substituted heterocyclic, whereinR²⁰ is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Aminocarbonyl” or the term “aminoacyl” refers to the group—C(O)NR²¹R²², wherein R²¹ and R²² independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Aminocarbonylamino” refers to the group —NR²¹C(O)NR²²R²³ where R²¹,R²², and R²³ are independently selected from hydrogen, alkyl, aryl orcycloalkyl, or where two R groups are joined to form a heterocyclylgroup.

The term “alkoxycarbonylamino” refers to the group —NRC(O)OR where eachR is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, andheterocyclyl are as defined herein.

The term “acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclyl-C(O)O— wherein alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,and heterocyclyl are as defined herein.

“Aminosulfonyl” refers to the group —SO₂NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and where R²¹ and R²²are optionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group and alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Sulfonylamino” refers to the group —NR²¹SO₂R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the atoms bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 18 carbon atoms having a single ring (such as is present in aphenyl group) or a ring system having multiple condensed rings (examplesof such aromatic ring systems include naphthyl, anthryl and indanyl)which condensed rings may or may not be aromatic, provided that thepoint of attachment is through an atom of an aromatic ring. This termincludes, by way of example, phenyl and naphthyl. Unless otherwiseconstrained by the definition for the aryl substituent, such aryl groupscan optionally be substituted with from 1 to 5 substituents, or from 1to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl,substituted cycloalkyl, substituted cycloalkenyl, amino, substitutedamino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.

“Aryloxy” refers to the group —O-aryl, wherein aryl is as definedherein, including, by way of example, phenoxy, naphthoxy, and the like,including optionally substituted aryl groups as also defined herein.

“Amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that atleast one R is not hydrogen.

The term “azido” refers to the group —N₃.

“Carboxyl,” “carboxy” or “carboxylate” refers to —CO₂H or salts thereof.

“Carboxyl ester” or “carboxy ester” or the terms “carboxyalkyl” or“carboxylalkyl” refers to the groups —C(O)O-alkyl, —C(O)O-substitutedalkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-aryl, —C(O)O-substituted aryl,—C(O)O-cycloalkyl, —C(O)O-substituted cycloalkyl, —C(O)O-cycloalkenyl,—C(O)O-substituted cycloalkenyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic,wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“(Carboxyl ester)oxy” or “carbonate” refers to the groups—O—C(O)O-alkyl, —O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl,—O—C(O)O-substituted alkenyl, —O—C(O)O— alkynyl, —O—C(O)O-substitutedalkynyl, —O—C(O)O-aryl, —O—C(O)O-substituted aryl, —O—C(O)O— cycloalkyl,—O—C(O)O-substituted cycloalkyl, —O—C(O)O-cycloalkenyl,—O—C(O)O-substituted cycloalkenyl, —O—C(O)O-heteroaryl,—O—C(O)O-substituted heteroaryl, —O—C(O)O-heterocyclic, and—O—C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Cyano” or “nitrile” refers to the group —CN.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving single or multiple cyclic rings including fused, bridged, andspiro ring systems. Examples of suitable cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyland the like. Such cycloalkyl groups include, by way of example, singlering structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclooctyl, and the like, or multiple ring structures such asadamantanyl, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, or from 1 to 3 substituents, selected fromalkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to10 carbon atoms having single or multiple rings and having at least onedouble bond and preferably from 1 to 2 double bonds.

The term “substituted cycloalkenyl” refers to cycloalkenyl groups havingfrom 1 to 5 substituents, or from 1 to 3 substituents, selected fromalkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 5 to 10carbon atoms having single or multiple rings and having at least onetriple bond.

“Cycloalkoxy” refers to —O-cycloalkyl.

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms,such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected fromthe group consisting of oxygen, nitrogen, and sulfur within the ring.Such heteroaryl groups can have a single ring (such as, pyridinyl,imidazolyl or furyl) or multiple condensed rings in a ring system (forexample as in groups such as, indolizinyl, quinolinyl, benzofuran,benzimidazolyl or benzothienyl), wherein at least one ring within thering system is aromatic and at least one ring within the ring system isaromatic, provided that the point of attachment is through an atom of anaromatic ring. In certain embodiments, the nitrogen and/or sulfur ringatom(s) of the heteroaryl group are optionally oxidized to provide forthe N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes,by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, andfuranyl. Unless otherwise constrained by the definition for theheteroaryl substituent, such heteroaryl groups can be optionallysubstituted with 1 to 5 substituents, or from 1 to 3 substituents,selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkoxy, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted cycloalkenyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂— alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl, andtrihalomethyl.

The term “heteroaralkyl” refers to the groups -alkylene-heteroaryl wherealkylene and heteroaryl are defined herein. This term includes, by wayof example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

“Heteroaryloxy” refers to —O-heteroaryl.

“Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl”refer to a saturated or unsaturated group having a single ring ormultiple condensed rings, including fused bridged and spiro ringsystems, and having from 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting ofnitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or moreof the rings can be cycloalkyl, aryl, or heteroaryl, provided that thepoint of attachment is through the non-aromatic ring. In certainembodiments, the nitrogen and/or sulfur atom(s) of the heterocyclicgroup are optionally oxidized to provide for the N-oxide, —S(O)—, or—SO₂— moieties.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, or from 1 to 3 substituents, selected from alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl,—SO₂-heteroaryl, and fused heterocycle.

“Heterocyclyloxy” refers to the group —O-heterocyclyl.

The term “heterocyclylthio” refers to the group heterocyclic-S—.

The term “heterocyclene” refers to the diradical group formed from aheterocycle, as defined herein.

The term “hydroxyamino” refers to the group —NHOH.

“Nitro” refers to the group —NO₂.

“Oxo” refers to the atom (═O).

“Sulfonyl” refers to the group SO₂-alkyl, SO₂-substituted alkyl,SO₂-alkenyl, SO₂-substituted alkenyl, SO₂-cycloalkyl, SO₂-substitutedcycloalkyl, SO₂-cycloalkenyl, SO₂-substituted cylcoalkenyl, SO₂-aryl,SO₂-substituted aryl, SO₂-heteroaryl, SO₂-substituted heteroaryl,SO₂-heterocyclic, and SO₂-substituted heterocyclic, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein. Sulfonyl includes, by way of example, methyl-SO₂—, phenyl-SO₂—,and 4-methylphenyl-SO₂—.

“Sulfonyloxy” refers to the group —OSO₂-alkyl, OSO₂-substituted alkyl,OSO₂-alkenyl, OSO₂-substituted alkenyl, OSO₂-cycloalkyl,OSO₂-substituted cycloalkyl, OSO₂-cycloalkenyl, OSO₂-substitutedcylcoalkenyl, OSO₂-aryl, OSO₂-substituted aryl, OSO₂-heteroaryl,OSO₂-substituted heteroaryl, OSO₂-heterocyclic, and OSO₂ substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

The term “aminocarbonyloxy” refers to the group —OC(O)NRR where each Ris independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Thioxo” or the term “thioketo” refers to the atom (═S).

“Alkylthio” or the term “thioalkoxy” refers to the group —S-alkyl,wherein alkyl is as defined herein. In certain embodiments, sulfur maybe oxidized to —S(O)—. The sulfoxide may exist as one or morestereoisomers.

The term “substituted thioalkoxy” refers to the group —S-substitutedalkyl.

The term “thioaryloxy” refers to the group aryl-S— wherein the arylgroup is as defined herein including optionally substituted aryl groupsalso defined herein.

The term “thioheteroaryloxy” refers to the group heteroaryl-S— whereinthe heteroaryl group is as defined herein including optionallysubstituted aryl groups as also defined herein.

The term “thioheterocyclooxy” refers to the group heterocyclyl-S—wherein the heterocyclyl group is as defined herein including optionallysubstituted heterocyclyl groups as also defined herein.

The term “pentafluorosulfanyl” refers to the group —SF₅.

In addition to the disclosure herein, the term “substituted,” when usedto modify a specified group or radical, can also mean that one or morehydrogen atoms of the specified group or radical are each, independentlyof one another, replaced with the same or different substituent groupsas defined below.

In addition to the groups disclosed with respect to the individual termsherein, substituent groups for substituting for one or more hydrogens(any two hydrogens on a single carbon can be replaced with ═O, ═NR⁷⁰,═N—OR⁷⁰, ═N₂ or ═S) on saturated carbon atoms in the specified group orradical are, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—NR⁸⁰R⁸⁰ trihalomethyl, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰,—SO₂O⁻M⁺, —SO₂OR⁷⁰, —OSO₂R⁷⁰, —OSO₂O⁻M⁺, —OSO₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰,—C(O)O⁻M⁺, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)O⁻M⁺, —OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰ isselected from the group consisting of optionally substituted alkyl,cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl, each R⁷⁰ is independentlyhydrogen or R⁶⁰; each R⁸⁰ is independently R⁷⁰ or alternatively, twoR⁸⁰'s, taken together with the nitrogen atom to which they are bonded,form a 5-, 6- or 7-membered heterocycloalkyl which may optionallyinclude from 1 to 4 of the same or different additional heteroatomsselected from the group consisting of O, N and S, of which N may have —Hor C₁-C₃ alkyl substitution; and each M⁺ is a counter ion with a netsingle positive charge. Each M⁺ may independently be, for example, analkali ion, such as K⁺, Na⁺, Li⁺; an ammonium ion, such as ⁺N(R⁶⁰)₄; oran alkaline earth ion, such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or[Ba²⁺]_(0.5) (“subscript 0.5 means that one of the counter ions for suchdivalent alkali earth ions can be an ionized form of a compound of theinvention and the other a typical counter ion such as chloride, or twoionized compounds disclosed herein can serve as counter ions for suchdivalent alkali earth ions, or a doubly ionized compound of theinvention can serve as the counter ion for such divalent alkali earthions). As specific examples, —NR⁸⁰R⁸⁰ is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl andN-morpholinyl.

In addition to the disclosure herein, substituent groups for hydrogenson unsaturated carbon atoms in “substituted” alkene, alkyne, aryl andheteroaryl groups are, unless otherwise specified, —R⁶⁰, halo, —O⁻M⁺,—OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰, trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺,—OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M+, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰,R⁷⁰, R⁸⁰ and M⁺ are as previously defined, provided that in case ofsubstituted alkene or alkyne, the substituents are not —O⁻M⁺, —OR⁷⁰,—SR⁷⁰, or —S⁻M⁺.

In addition to the groups disclosed with respect to the individual termsherein, substituent groups for hydrogens on nitrogen atoms in“substituted” heteroalkyl and cycloheteroalkyl groups are, unlessotherwise specified, —R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰,trihalomethyl, —CF₃, —CN, —NO, —NO₂, —S(O)₂R⁷⁰, —S(O)₂O⁻M⁺, —S(O)₂R⁷⁰,—OS(O)₂R⁷⁰, —OS(O)₂O⁻M⁺, —OS(O)₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺,—P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —C(O)OR⁷⁰,—C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰,—OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰C(O)OR⁷⁰,—NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined.

In addition to the disclosure herein, in a certain embodiment, a groupthat is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3substituents, 1 or 2 substituents, or 1 substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,which is further substituted by a substituted aryl group, etc.) are notintended for inclusion herein. In such cases, the maximum number of suchsubstitutions is three. For example, serial substitutions of substitutedaryl groups specifically contemplated herein are limited to substitutedaryl-(substituted aryl)-substituted aryl.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

As to any of the groups disclosed herein which contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, the subjectcompounds include all stereochemical isomers arising from thesubstitution of these compounds.

The term “pharmaceutically acceptable salt” means a salt which isacceptable for administration to a patient, such as a mammal (salts withcounterions having acceptable mammalian safety for a given dosageregime). Such salts can be derived from pharmaceutically acceptableinorganic or organic bases and from pharmaceutically acceptableinorganic or organic acids. “Pharmaceutically acceptable salt” refers topharmaceutically acceptable salts of a compound, which salts are derivedfrom a variety of organic and inorganic counter ions well known in theart and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, formate, tartrate, besylate,mesylate, acetate, maleate, oxalate, and the like.

The term “salt thereof” means a compound formed when a proton of an acidis replaced by a cation, such as a metal cation or an organic cation andthe like. Where applicable, the salt is a pharmaceutically acceptablesalt, although this is not required for salts of intermediate compoundsthat are not intended for administration to a patient. By way ofexample, salts of the present compounds include those wherein thecompound is protonated by an inorganic or organic acid to form a cation,with the conjugate base of the inorganic or organic acid as the anioniccomponent of the salt.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.When the solvent is water, the solvate formed is a hydrate.

“Stereoisomer” and “stereoisomers” refer to compounds that have sameatomic connectivity but different atomic arrangement in space.Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers,and diastereomers.

“Tautomer” refers to alternate forms of a molecule that differ only inelectronic bonding of atoms and/or in the position of a proton, such asenol-keto and imine-enamine tautomers, or the tautomeric forms ofheteroaryl groups containing a —N═C(H)—NH— ring atom arrangement, suchas pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Aperson of ordinary skill in the art would recognize that othertautomeric ring atom arrangements are possible.

It will be appreciated that the term “or a salt or solvate orstereoisomer thereof” is intended to include all permutations of salts,solvates and stereoisomers, such as a solvate of a pharmaceuticallyacceptable salt of a stereoisomer of subject compound.

“Pharmaceutically effective” and “therapeutically effective” refer to acompound (e.g., active agent) used to treat a specified disorder ordisease or one or more of its symptoms and/or to prevent the occurrenceof the disease or disorder. For example, in reference to tumorigenicproliferative disorders, treatment with a pharmaceutically ortherapeutically effective compound (active agent) is sufficient to,among other things, cause the tumor to shrink or decrease the growthrate of the tumor.

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound (e.g., active agent) sufficientto treat a specified disorder or disease or one or more of its symptomsand/or to prevent the occurrence of the disease or disorder. Forexample, in reference to tumorigenic proliferative disorders, apharmaceutically or therapeutically effective amount comprises an amountsufficient to, among other things, cause the tumor to shrink or decreasethe growth rate of the tumor.

“Patient” refers to human and non-human subjects, especially mammaliansubjects.

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition in a patient, such as amammal (particularly a human) that includes: (a) preventing the diseaseor medical condition from occurring, such as, prophylactic treatment ofa subject; (b) ameliorating the disease or medical condition, such as,eliminating or causing regression of the disease or medical condition ina patient; (c) suppressing the disease or medical condition, for exampleby, slowing or arresting the development of the disease or medicalcondition in a patient; or (d) alleviating a symptom of the disease ormedical condition in a patient.

Representative Embodiments

The following substituents and values are intended to providerepresentative examples of various aspects and embodiments. Theserepresentative values are intended to further define and illustrate suchaspects and embodiments and are not intended to exclude otherembodiments or to limit the scope of the present disclosure. In thisregard, the representation that a particular value or substituent ispreferred is not intended in any way to exclude other values orsubstituents from the present disclosure unless specifically indicated.

These compounds may contain one or more chiral centers and therefore,the embodiments are directed to racemic mixtures; pure stereoisomers(i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures andthe like unless otherwise indicated. When a particular stereoisomer isshown or named herein, it will be understood by those skilled in the artthat minor amounts of other stereoisomers may be present in thecompositions unless otherwise indicated, provided that the desiredutility of the composition as a whole is not eliminated by the presenceof such other isomers.

The compositions of the present disclosure include compounds as shownbelow. Pharmaceutical compositions and methods of the present disclosurealso contemplate compounds as provided herein.

Embodiments of the present disclosure include a compound having atetrazolone derivative of a carboxyl group of an active agent. By“derivative” is meant a compound that can be produced from a precursorcompound by a chemical process. For example, an atom or group of atomsin the precursor compound can be modified or replaced to produce thederivative compound (also referred to herein as an “analog” or“structural analog”). In certain embodiments, an active agent includes acarboxyl group. Compounds of the present disclosure may be derivativesof an active agent that includes a carboxyl group. In certainembodiments, the carboxyl group of the active agent is modified orreplaced to produce the derivative. For example, the carboxyl group ofthe active agent may be modified or replaced with a tetrazolone or asubstituted tetrazolone. In these embodiments, the compounds of thepresent disclosure include a tetrazolone (or substituted tetrazolone)derivative of a carboxyl group of the active agent. As such, aspects ofthe present disclosure include compounds having a tetrazolone orsubstituted tetrazolone produced from a carboxyl group of an activeagent.

In certain embodiments, the tetrazolone derivative is produced from acarboxyl group of the active agent. The carboxyl group of the activeagent may be modified or replaced to form the tetrazolone derivative. Insome cases, the carboxyl group is modified to produce one or moreintermediate groups before producing the tetrazolone derivative. Incertain instances, such intermediate groups include, but are not limitedto, an acyl halide (i.e., acid halide), an isocyanate, an acyl azide,and the like. In some embodiments, the acyl halide intermediate is anacyl chloride (acid chloride).

In certain embodiments, the tetrazolone derivative includes atetrazolone or a substituted tetrazolone. By “tetrazolone” is meant atetrazol-5-one group. In some cases, the tetrazolone derivative istetrazolone (e.g., an unsubstituted tetrazolone, such as a tetrazolonethat has a hydrogen at the 4-position). In some cases, the tetrazolonederivative is a substituted tetrazolone, such as a 1,4-disubstitutedtetrazolone. Substituents of interest include, but are not limited to,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, andsubstituted alkynyl.

In certain embodiments, the substituted tetrazolone includes an alkylsubstituent, such as, but not limited to a C₁₋₆ alkyl, a C₁₋₅ alkyl,C₁₋₄ alkyl, C₁₋₃ alkyl, or C₁₋₂ alkyl. In some embodiments, thesubstituted tetrazolone includes a C₁₋₃ alkyl, such as methyl. Incertain embodiments, the substituted tetrazolone includes a substitutedalkyl substituent, such as, but not limited to a substituted C₁₋₆ alkyl,a substituted C₁₋₅ alkyl, substituted C₁₋₄ alkyl, substituted C₁₋₃alkyl, or substituted C₁₋₂ alkyl. In some embodiments, the substitutedtetrazolone includes a substituted C₁₋₃ alkyl, such as substitutedmethyl.

In certain embodiments, the substituted tetrazolone includes an alkenylsubstituent, such as, but not limited to a C₁₋₆ alkenyl, a C₁₋₅ alkenyl,C₁₋₄ alkenyl, C₁₋₃ alkenyl, or C₁₋₂ alkenyl. In some embodiments, thesubstituted tetrazolone includes a C₁₋₃ alkenyl. In certain embodiments,the substituted tetrazolone includes a substituted alkenyl substituent,such as, but not limited to a substituted C₁₋₆ alkenyl, a substitutedC₁₋₅ alkenyl, substituted C₁₋₄ alkenyl, substituted C₁₋₃ alkenyl, orsubstituted C₁₋₂ alkenyl. In some embodiments, the substitutedtetrazolone includes a substituted C₁₋₃ alkenyl.

In certain embodiments, the substituted tetrazolone includes an alkynylsubstituent, such as, but not limited to a C₁₋₆ alkynyl, a C₁₋₅ alkynyl,C₁₋₄ alkynyl, C₁₋₃ alkynyl, or C₁₋₂ alkynyl. In some embodiments, thesubstituted tetrazolone includes a C₁₋₃ alkynyl. In certain embodiments,the substituted tetrazolone includes a substituted alkynyl substituent,such as, but not limited to a substituted C₁₋₆ alkynyl, a substitutedC₁₋₅ alkynyl, substituted C₁₋₄ alkynyl, substituted C₁₋₃ alkynyl, orsubstituted C₁₋₂ alkynyl. In some embodiments, the substitutedtetrazolone includes a substituted C₁₋₃ alkynyl.

In certain embodiments, the compound is of the following formula:

wherein

R¹ is the active agent; and

R² is selected from hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl;

or a salt or stereoisomer thereof.

In certain embodiments, R¹ is the active agent. In some cases, theactive agent is an agrochemical, such as an herbicide. In someinstances, the active agent is a therapeutically effective active agent.For example, R¹ may be any of the active agents described below. Asdiscussed herein, a carboxyl group of the active agent may be replacedby a bond between R¹ and the tetrazolone or substituted tetrazolonegroup, as shown in the formula above.

In some embodiments, R² is selected from hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl. Insome embodiments, R² is hydrogen. In some embodiments, R² is alkyl orsubstituted alkyl. In some embodiments, R² is alkenyl or substitutedalkenyl. In some embodiments, R² is alkynyl or substituted alkynyl.

In some embodiments, R² is hydrogen, alkyl or substituted alkyl. In someembodiments, R² is hydrogen or alkyl. In some embodiments, R² is alkyl(e.g., methyl).

In certain embodiments, R² is alkyl, such as, but not limited to a C₁₋₆alkyl, C₁₋₅ alkyl, C₁₋₄ alkyl, C₁₋₃ alkyl, or C₁₋₂ alkyl. In someembodiments, R² is C₁₋₃ alkyl, such as methyl. In certain embodiments,R² is substituted alkyl, such as substituted C₁₋₆ alkyl, substitutedC₁₋₅ alkyl, substituted C₁₋₄ alkyl, substituted C₁₋₃ alkyl, orsubstituted C₁₋₂ alkyl. In some embodiments, R² is substituted C₁₋₃alkyl, such as substituted methyl.

In certain embodiments, R² is alkenyl, such as, but not limited to aC₁₋₆ alkenyl, C₁₋₅ alkenyl, C₁₋₄ alkenyl, C₁₋₃ alkenyl, or C₁₋₂ alkenyl.In some embodiments, R² is C₁₋₃ alkenyl. In certain embodiments, R² issubstituted alkenyl, such as, but not limited to a substituted C₁₋₆alkenyl, substituted C₁₋₅ alkenyl, substituted C₁₋₄ alkenyl, substitutedC₁₋₃ alkenyl, or substituted C₁₋₂ alkenyl. In some embodiments, R² issubstituted C₁₋₃ alkenyl.

In certain embodiments, R² is alkynyl, such as, but not limited to aC₁₋₆ alkynyl, a C₁₋₅ alkynyl, C₁₋₄ alkynyl, C₁₋₃ alkynyl, or C₁₋₂alkynyl. In some embodiments, R² is C₁₋₃ alkynyl. In certainembodiments, R² is substituted alkynyl, such as, but not limited to asubstituted C₁₋₆ alkynyl, substituted C₁₋₅ alkynyl, substituted C₁₋₄alkynyl, substituted C₁₋₃ alkynyl, or substituted C₁₋₂ alkynyl. In someembodiments, R² is substituted C₁₋₃ alkynyl.

In certain embodiments, the compound is optically active. In certainembodiments, there is an enantiomeric excess of 90% or more. In certainembodiments, there is an enantiomeric excess of 95% or more. In certainembodiments, there is an enantiomeric excess of 99% or more.

Particular compounds of interest, and salts or solvates or stereoisomersthereof, include:

In certain embodiments, compounds of the present disclosure areisosteres (e.g., bioisosteres) of active agents that include a carboxylgroup. By “isostere” or “bioisostere” is meant a derivative of an activeagent (e.g., a therapeutically effective active agent), where thederivative produces substantially similar biological effects in vivo ascompared to the active agent. In some embodiments, compounds of thepresent disclosure include a tetrazolone or substituted tetrazolone andare isosteres (e.g., bioisosteres) of an active agent (e.g., atherapeutically effective active agent) that includes a carboxyl group.

As described herein, a compound of the present disclosure may be atetrazolone derivative of an active agent (or prodrug of an activeagent), such as a tetrazolone-containing isostere or bioisostere of anactive agent (or prodrug of an active agent) having a carboxyl group. Insome instances, the active agent is a biologically active agent, suchas, but not limited to, a pesticide, an herbicide or a therapeuticallyeffective compound. In some embodiments, the active agent is atherapeutically effective active agent, such as, but not limited to thefollowing:

The compounds described herein also include isotopically labeledcompounds where one or more atoms have an atomic mass different from theatomic mass conventionally found in nature. Examples of isotopes thatmay be incorporated into the compounds disclosed herein include, but arenot limited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Thus, thedisclosed compounds may be enriched in one or more of these isotopesrelative to the natural abundance of such isotope. By way of example,deuterium (²H) has a natural abundance of about 0.015%. Accordingly, forapproximately every 6,500 hydrogen atoms occurring in nature, there isone deuterium atom. Specifically contemplated herein are compoundsenriched in deuterium at one or more positions. Thus, deuteriumcontaining compounds of the disclosure have deuterium at one or morepositions (as the case may be) in an abundance of greater than 0.015%.

General Synthetic Procedures

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith and March, March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Fifth Edition,Wiley-Interscience, 2001; or Vogel, A Textbook of Practical OrganicChemistry, Including Qualitative Organic Analysis, Fourth Edition, NewYork: Longman, 1978).

Compounds as described herein can be purified by any purificationprotocol known in the art, including chromatography, such as HPLC,preparative thin layer chromatography, flash column chromatography andion exchange chromatography. Any suitable stationary phase can be used,including normal and reversed phases as well as ionic resins. In certainembodiments, the disclosed compounds are purified via silica gel and/oralumina chromatography. See, e.g., Introduction to Modern LiquidChromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, JohnWiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl,Springer-Verlag, New York, 1969.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas J. F. W. McOmie, “Protective Groups in Organic Chemistry”, PlenumPress, London and New York 1973, in T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer),Academic Press, London and New York 1981, in “Methoden der organischenChemie”, Houben-Weyl, 4^(th) edition, Vol. 15/1, Georg Thieme Verlag,Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide,Proteine”, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982,and/or in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide andDerivate”, Georg Thieme Verlag, Stuttgart 1974. The protecting groupsmay be removed at a convenient subsequent stage using methods known fromthe art.

Examples of synthetic methods for the compounds provided herein aredescribed in the schemes below. These methods can be adapted tosynthesize compounds and prodrugs described herein.

Synthesis of Compounds

In certain embodiments, the compounds can be synthesized according toone or more of the steps of the scheme shown below:

where compound 10 is a carboxylic acid-containing compound of interest,compound 12 includes an activated acyl group (e.g., X is an acylactivating group, such as a leaving group), acyl azide compound 13 andisocyanate compound 14 may be formed in situ or may be isolated startingcompounds, and tetrazolone 16 may be optionally further derivatizedusing any convenient method, e.g., with an alkylating agent to produceto tetrazolone 17, where R′ is an alkyl or a substituted alkyl group.The selection of a suitable starting compound depends on a variety offactors, such as the desired product. Alternatively, compound 10 may beconverted directly to intermediate acyl azide compound 13 via a singlereagent, such as diphenyl phosphoryl azide.

In some embodiments, R—CO₂H (10) is a bioactive compound of interest(e.g., as described herein). Bioactive compounds of interest which maybe converted into tetrazolone compounds according to the methodsdescribed herein include, but are not limited to, amino acids, peptides,nutrients (e.g., Vitamin B), natural products or semi-synthetic drugs(e.g., penicillins, cephalosporins, carbapenems, etc.), antibiotics,such as quinolone antibiotics (e.g., Ciprofloxacin, ABT-492) orquinazolinone antibiotics (e.g.,(E)-3-(2-(4-cyanostyryl)-4-oxoquinazolin-3(4H)-yl)benzoic acid), insulinsecretors, such as “Metliginides” (e.g., Repaglinide), non-steroidalanti-inflammatories (e.g., Ibuprofen, Naproxen, etc.), “Statins” (e.g.,Atorvastatin), CFTR “Correctors” & Read-Through Enablers for nmStops(e.g., Lumacaftor (VX-809)/Ataluren) and antiviral compounds (e.g.,Elvitegravir (GS-9137)). In some instances, rather than converting acarboxylic acid group of a carboxylic acid-containing active agent to atetrazolone group, the tetrazolone derivative of the active agent may besynthesized using a tetrazolone-containing precursor.

In certain embodiments, R is a fragment or a synthetic precursor of acompound of interest and may further include any convenient additionalfunctional groups (e.g., protected or unprotected functional groups)suitable for use in the synthesis of compounds of interest. A variety ofchemical synthetic schemes and conditions useful for synthesizing suchcompounds are available. As such, the tetrazolone group of the subjectcompounds may be installed at any convenient point in the synthesis of atarget compound of interest. In some instances, the tetrazolone group isinstalled at the end of the synthesis, e.g., where R represents abioactive moiety, or a protected version thereof. In certain instances,the tetrazolone group is installed into a compound R, which is aconvenient fragment or precursor of a target compound of interest.

Any convenient tetrazolone precursor of scheme 1 (i.e., compounds 10,12, 13 or 14 including any convenient R group of interest) may beutilized as a starting compound in the preparation of the subjecttetrazolone compound 16. In some cases, one of compounds 12, 13 or 14 isprovided as a starting compound for the synthesis of compound 16, wherethe compounds 12, 13 or 14 may be derived from a carboxylic acid (10) orfrom another convenient precursor.

R may include any convenient additional functional groups (e.g.,protected or unprotected functional groups), that are stable to themethods of preparing the subject tetrazolone compounds. In someembodiments, R includes one or more functional groups selected from ahalide, a ketone and a nitrile.

In certain embodiments, the tetrazolone is prepared from compound 12. Insome instances of compound 12, X is selected from the group consistingof halogen (e.g., fluoro, chloro, bromo or iodo), azide and a leavinggroup of an active ester. In certain embodiments of compound 12, X isazide (i.e., N₃). In certain embodiments of compound 12, X is a leavinggroup of an active ester, such as an alkoxy, aryloxy, heteroaryloxy or aN-hydroxysuccinimidyl group (e.g., NHS). In certain embodiments ofcompound 12, X is chloro.

In some embodiments of Scheme 1, tetrazolone 17 is produced from totetrazolone 16 via reaction with an alkylating agent. Any convenientalkylating agents and methods of using the same may be adapted toderivatize the subject tetraolone compounds. Alkylating agents ofinterest include, but are not limited to, alkyl halides, alkylsulfonates, Michael acceptor reagents, In certain embodiments, thealkylating agent is methyl iodide. In certain cases, the alkylatingagent may be used in conjunction with a basic reagent, such as potassiumcarbonate, in any convenient solvent.

In some embodiments, the compounds can be synthesized as shown below:

where compound 15 is an acid chloride that is converted to a tetrazolonecompound 16 using an azide agent as described herein. The acid chloridecompound may be prepared from any convenient starting materialsaccording to any convenient method. In some cases, the acid chloride 15is prepared (directly or indirectly) from a carboxylic acid containingcompound of interest, e.g., as shown in scheme 1.

In some embodiments of schemes 1 and 2, R may be any convenient aryl,heteroaryl or heterocycle group, where R may be further substituted withone or more substituents. In some embodiments, compound 15 is an aryl orheteroaryl acid chloride. In some instances, R is a phenyl orsubstituted phenyl. In certain embodiments, R is a substituted biphenylor a biphenyl. In certain embodiments, R is a pyridyl or a substitutedpyridyl. In certain embodiments, R is an anthracene, a substitutedanthracene, a naphthalene or a substituted naphthalene. In certaininstances, R is a 5-membered heterocyclyl, such as a thienyl, a furanyl,an oxazole or an isooxazole. R may include a variety of additionalsubstitutents. Any convenient electron rich or electron poor R aromaticgroups may be utilized. In some embodiments, R further includes one ormore substituents selected from the group consisting of alkyl,substituted alkyl, nitro, halogen, acyl, cyano, sulfonyl, alkylthio,alkoxy, substituted alkoxy, acyloxy, aralkyl, substituted aralkyl,heterocyclylalkyl, substituted heterocyclylalkyl, heteroarylalkyl,substituted heteroarylalkyl, aminosulfonyl, alkenyl, substitutedalkenyl, heteroaryl, substituted heteroaryl, aryl and substituted aryl.In certain embodiments, R further includes one or more substituentsselected from the group consisting of tert-butyl, trifluoromethyl,nitro, fluoro, bromo, chloro, iodo, acetyl, cyano, pentafluorosulfanyl(e.g., —SF₅), methylthio, acetoxy, diethylaminosulfonyl and2-chlorophenyl.

In certain embodiments of schemes 1 and 2, R is described by theformula:

where each A is independently N or CR where R is H or a substituent. Incertain instances, each R is independently selected from the groupconsisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkoxy, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted cycloalkenyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl. Insome embodiments, R is selected from the group consisting of alkyl,substituted alkyl, nitro, halogen, acyl, cyano, sulfonyl, alkylthio,alkoxy, substituted alkoxy, acyloxy, aralkyl, substituted aralkyl,heterocyclylalkyl, substituted heterocyclylalkyl, heteroarylalkyl,substituted heteroarylalkyl, aminosulfonyl, alkenyl, substitutedalkenyl, heteroaryl, substituted heteroaryl, aryl and substituted aryl.In certain embodiments, R is selected from the group consisting oftert-butyl, trifluoromethyl, nitro, fluoro, bromo, chloro, iodo, acetyl,cyano, pentafluorosulfanyl (e.g., —SF₅), methylthio, acetoxy,diethylaminosulfonyl and 2-chlorophenyl.

In certain embodiments of schemes 1 and 2, R is described by one of thefollowing formulae:

where R¹¹-R¹⁵ are independently selected from the group consisting ofhydrogen, acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkoxy, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted cycloalkenyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂— alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl. Insome embodiments, R¹¹-R¹⁵ are independently selected from the groupconsisting of alkyl, substituted alkyl, nitro, halogen, acyl, cyano,sulfonyl, alkylthio, alkoxy, substituted alkoxy, acyloxy, aralkyl,substituted aralkyl, heterocyclylalkyl, substituted heterocyclylalkyl,heteroarylalkyl, substituted heteroarylalkyl, aminosulfonyl, alkenyl,substituted alkenyl, heteroaryl, substituted heteroaryl, aryl andsubstituted aryl. In certain embodiments, R¹¹-R¹⁵ are independentlyselected from the group consisting of tert-butyl, trifluoromethyl,nitro, fluoro, bromo, chloro, iodo, acetyl, cyano, pentafluorosulfanyl(e.g., —SF₅), methylthio, acetoxy, diethylaminosulfonyl and2-chlorophenyl.

In certain embodiments of schemes 1 and 2, R is described by one of thefollowing formulae:

where R¹-R¹⁶ are as described above for R¹-R¹⁵.

In some embodiments of schemes 1 and 2, R may be any convenient alkyl,substituted alkyl, alkenyl or substituted alkenyl. In certainembodiments, R is an alkyl (e.g., methyl, ethyl, propyl, butyl). Incertain embodiments, R is a substituted alkyl (e.g., isopropyl,tert-butyl). In certain embodiments, R is alkenyl. In certainembodiments, R is a substituted alkenyl (e.g., a substituted ethenylgroup). In some embodiments, R further includes one or more substituentsselected from the group consisting of alkyl, substituted alkyl, nitro,halogen, acyl, cyano, sulfonyl, alkylthio, alkoxy, substituted alkoxy,acyloxy, aralkyl, substituted aralkyl, heterocyclylalkyl, substitutedheterocyclylalkyl, heteroarylalkyl, substituted heteroarylalkyl,aminosulfonyl, alkenyl, substituted alkenyl, heteroaryl, substitutedheteroaryl, aryl and substituted aryl. In certain embodiments, R furtherincludes one or more substituents selected from the group consisting oftert-butyl, trifluoromethyl, nitro, fluoro, bromo, chloro, iodo, acetyl,cyano, pentafluorosulfanyl (e.g., —SF₅), methylthio, acetoxy,diethylaminosulfonyl and 2-chlorophenyl.

Exemplary starting materials and tetrazolone compounds which may beprepared according to the methods described herein are show in Table A.

TABLE A Tetrazolone formation from acid chloride Entry Starting MaterialProduct 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

Azide Agents

For the synthesis of tetrazolone compounds, e.g., via scheme 1 or 2, anyconvenient azido agents may be utilized. As used herein, the term azideagent is used to refer to both stable commercially available reagentsthat are utilized in the subject methods, and transient azido reagentsthat may be formed in situ and are involved in the preparation of thesubject tetrazolone compounds, e.g., in situ reagent formed by thecombination of two or more starting agents. Azide agents of interestinclude, but are not limited to, an inorganic azide and a lewis acid,such as sodium azide/aluminium chloride; an organic azido reagent, suchas an azido silane; and hydrazoic acid (HN₃). In some instances, theazide agent is provided using one or more agents selected from the groupconsisting of sodium azide, trimethylsilyl azide, imidazole-1-sulfonylazide, trifluoromethanesulfonyl azide, and hydrazoic acid. In certainembodiments, the azide agent may be provided using an additional agentsuch as a Bronsted or Lewis acid, e.g., aluminium chloride, TiCl₄,SiCl₄, phosphorus pentachloride, BF₃, OEt₂, etc. In some embodiments,the azide agent is an azido silane (i.e., a silyl azide). In certainembodiments, the azide agent is trimethylsilyl azide (TMSN₃). In somecases, the azide agent is provided or pre-formed using a convenientmethod and then added to the reaction mixture of the subject methods. Inother cases, the azide agent is formed in situ by adding two or morereagents to a reaction mixture that are capable of forming the azideagent of interest.

The subject methods of preparing a tetrazolone using an azide agent,e.g., as described in scheme 2, may be performed under any convenientreaction conditions that provide for production of the targettetrazolones. It is understood that a variety of reaction conditionssuch as solvent, temperature, pressure, microwave, flow chemistry,concentration, equivalents or stoichiometry of reagents and time may beadjusted as needed according to any convenient methods known in the art.

The subject methods of preparing a tetrazolone using an azide agent,e.g., as described in scheme 2, may be performed using any convenientsolvents. In certain embodiments, the azide agent itself is utilized asa solvent. In certain instances, the azide agent is dissolved in anorganic solvent. In certain embodiments, the reaction mixture, e.g., ofscheme 2, includes 3.0 equivalents or more of the azide agent relativeto the starting material, e.g., compound 5 of scheme 2, such as 3.5equivalent or more, 4.0 equivalents or more, 4.5 equivalents or more,5.0 equivalents or more, 5.5 equivalents or more, 6.0 equivalents ormore, 6.5 equivalents or more, 7.0 equivalents or more, 8.0 equivalentsor more, 9.0 equivalents or more, 10 equivalents or more, 20 equivalentsor more, or even more.

The subject methods of preparing a tetrazolone using an azide agent,e.g., as described in scheme 2, may be performed at any convenienttemperature and for any convenient length of time. In certainembodiments, the reaction mixture, e.g., of scheme 2, is heated at 50°C. or more, such as 60° C. or more, 70° C. or more, 80° C. or more, 90°C. or more, 100° C. or more, 110° C. or more, or even more, for a periodof time sufficient to convert starting material (e.g., compound 15) totetrazolone (16). Any convenient methods of monitoring the reaction maybe utilized to assess the degree of completion, such as thin layerchromatography, HPLC, NMR, and the like.

In certain embodiments, tetrazolone compounds as described herein areprepared by adapting procedures known to those skilled in the art. Anyconvenient methods and materials may be adapted for use in thepreparation of the subject compounds. Methods and materials of interestinclude, but are not limited to those described by, Singh et al., U.S.2011/0130415, the disclosure of which is herein incorporated byreference in its entirety.

In some embodiments, the tetrazolone of the subject compound is preparedfrom an isocyanate precursor by reaction with an azide agent. Anyconvenient azide agents may be utilized. Azide agents of interestinclude but are not limited to, an inorganic azide and a lewis acid,such as sodium azide/aluminium chloride; an organic azido reagent, suchas silyl azide, e.g. azidotrimethylsilane. The isocyanate precursors maybe prepared using any convenient methods. Methods and materials ofinterest that may be apapted for use in the preparation of isocyanateprecurors include, but are not limited to, those methods and materialsdescribed by Singh et al., U.S. 2011/0130415, the disclosure of which isherein incorporated by reference in its entirety. Any convenient organicsolvents may be utilized in these methods of preparation. The methodsmay be performed at a variety of temperatures. In some cases, themethods are performed at room temperature. In some cases, the methodsare performed with heating. In certain cases, the methods are performedat a temperature within 20° C. of the boiling point of the solvent, suchas within 10° C. of the boiling point.

In certain embodiments, stereoisomers of compounds can be isolated byprocedures known to those skilled in the art. The individualstereoisomers may be obtained, for instance, by a resolution techniqueor by chromatography techniques (e.g., silica gel chromatography, chiralchromatography, etc.).

Although the synthetic schemes discussed above may not illustrate theuse of protecting groups, skilled artisans will recognize that in someinstances certain substituents may include functional groups requiringprotection. The exact identity of the protecting group used will dependupon, among other things, the identity of the functional group beingprotected and the reaction conditions used in the particular syntheticscheme, and will be apparent to those of skill in the art. Guidance forselecting protecting groups, their attachment and removal suitable for aparticular application can be found, for example, in Greene & Wuts,supra.

Prodrugs as described herein can be prepared by routine modification ofthe above-described methods. Alternatively, such prodrugs can beprepared by reacting a suitably protected compound with a suitableprogroup. Conditions for carrying out such reactions and fordeprotecting the product to yield prodrugs as described herein arewell-known.

Pharmaceutical Compositions

In certain embodiments, the disclosed compounds are useful for thetreatment of a disease or disorder. Accordingly, pharmaceuticalcompositions comprising at least one disclosed compound are alsodescribed herein. In some instances, the pharmaceutical compositionincludes a compound of the present disclosure and a pharmaceuticallyacceptable carrier. In some cases, the pharmaceutical compositionincludes a therapeutically effective amount of compound of the presentdisclosure or a pharmaceutically acceptable salt or solvate orstereoisomer thereof, and a pharmaceutically acceptable carrier.

A disclosed compound can be administered alone, as the sole activepharmaceutical agent in the pharmaceutical composition, or incombination with one or more additional compounds of the presentdisclosure or in conjunction with other active agents. When administeredas a combination, the therapeutic agents can be formulated as separatecompositions that are administered simultaneously or at different times,or the therapeutic agents can be administered together as a singlecomposition combining two or more therapeutic agents. Thus, thepharmaceutical compositions disclosed herein containing a compound ofthe present disclosure optionally include other therapeutic agents.Accordingly, certain embodiments are directed to such pharmaceuticalcompositions, where the composition further includes a therapeuticallyeffective amount of an agent selected as is known to those of skill inthe art.

Examples of such pharmaceutical compositions that include two or moreactive agents are pharmaceutical compositions having two or morecompounds of the present disclosure. Other examples of pharmaceuticalcomposition that include two or more active agents are pharmaceuticalcompositions having a compound of the present disclosure in conjunctionwith another active agent. For example, a pharmaceutical composition mayinclude a compound of the present disclosure and an antihypertensiveactive agent, such as, but not limited to sacubitril or a prodrugthereof.

In certain embodiments, a pharmaceutical composition may include anantihypertensive active agent, such as sacubitril, and a compound of thepresent disclosure, such as, but not limited to:

In certain embodiments, pharmaceutical compositions that include twoactive agents have a ratio (w/w) of a first active agent to a secondactive agent of 10:1, or 9:1, or 8:1, or 7:1, or 6:1, or 5:1, or 4:1, or3:1, or 2:1, or 1:1, or 1:2, or 1:3, or 1:4, or 1:5, or 1:6, or 1:7, or1:8, or 1:9, or 1:10. In some cases, pharmaceutical compositions thatinclude two active agents have a ratio (w/w) of a first active agent toa second active agent of 1:1.

A pharmaceutical composition that includes a subject compound may beadministered to a patient alone, or in combination with othersupplementary active agents as described above. The pharmaceuticalcompositions may be manufactured using any of a variety of processes,including, but not limited to, conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping, lyophilizing, and the like. The pharmaceutical compositioncan take any of a variety of forms including, but not limited to, asterile solution, suspension, emulsion, lyophilisate, tablet, pill,pellet, capsule, powder, syrup, elixir or any other dosage form suitablefor administration.

A subject compound may be administered to a subject using any convenientmeans capable of resulting in the desired reduction in disease conditionor symptom. Thus, a subject compound can be incorporated into a varietyof formulations for therapeutic administration. More particularly, asubject compound can be formulated into pharmaceutical compositions bycombination with appropriate pharmaceutically acceptable carriers ordiluents, and may be formulated into preparations in solid, semi-solid,liquid or gaseous forms, such as tablets, capsules, powders, granules,ointments, solutions, suppositories, injections, inhalants, aerosols,and the like.

Formulations for pharmaceutical compositions are described in, forexample, Remington's Pharmaceutical Sciences, by E. W. Martin, MackPublishing Co., Easton, Pa., 19th Edition, 1995, which describesexamples of formulations (and components thereof) suitable forpharmaceutical delivery of disclosed compounds. Pharmaceuticalcompositions that include at least one of the subject compounds can beformulated for use in human or veterinary medicine. Particularformulations of a disclosed pharmaceutical composition may depend, forexample, on the mode of administration and/or on the location of thesubject to be treated. In some embodiments, formulations include apharmaceutically acceptable carrier in addition to at least one activeingredient, such as a subject compound. In other embodiments, othermedicinal or pharmaceutical agents, for example, with similar, relatedor complementary effects on the disease or condition being treated canalso be included as active ingredients in a pharmaceutical composition.

Pharmaceutically acceptable carriers useful for the disclosed methodsand compositions may depend on the particular mode of administrationbeing employed. For example, parenteral formulations may includeinjectable fluids, such as, but not limited to, pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. For solid compositions (e.g., powder, pill, tablet, or capsuleforms), non-toxic solid carriers can include, for example,pharmaceutical grades of mannitol, lactose, starch, or magnesiumstearate. In addition to biologically neutral carriers, pharmaceuticalcompositions to be administered can optionally contain minor amounts ofnon-toxic auxiliary substances (e.g., excipients), such as wetting oremulsifying agents, preservatives, and pH buffering agents and the like;for example, sodium acetate or sorbitan monolaurate. Other examples ofexcipients include, nonionic solubilizers, such as cremophor, orproteins, such as human serum albumin or plasma preparations.

Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) water (e.g., pyrogen-free water); (17) isotonic saline; (18)Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

The disclosed pharmaceutical compositions may be formulated as apharmaceutically acceptable salt of a disclosed compound.Pharmaceutically acceptable salts are non-toxic salts of a free baseform of a compound that possesses the desired pharmacological activityof the free base. These salts may be derived from inorganic or organicacids. Non-limiting examples of suitable inorganic acids arehydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid,hydroiodic acid, and phosphoric acid. Non-limiting examples of suitableorganic acids are acetic acid, propionic acid, glycolic acid, lacticacid, pyruvic acid, malonic acid, succinic acid, malic acid, maleicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, methylsulfonic acid, salicylic acid, formic acid, trichloroacetic acid,trifluoroacetic acid, gluconic acid, asparagic acid, aspartic acid,benzenesulfonic acid, para-toluenesulfonic acid, naphthalenesulfonicacid, and the like. In certain embodiments, the pharmaceuticallyacceptable salt includes formic acid. In certain embodiments, thepharmaceutically acceptable salt includes trifluoroacetic acid. Othersuitable pharmaceutically acceptable salts are found in Remington'sPharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton,Pa., 1985. A pharmaceutically acceptable salt may also serve to adjustthe osmotic pressure of the composition.

A subject compound can be used alone or in combination with appropriateadditives to make tablets, powders, granules or capsules, for example,with conventional additives, such as lactose, mannitol, corn starch orpotato starch; with binders, such as crystalline cellulose, cellulosederivatives, acacia, corn starch or gelatins; with disintegrators, suchas corn starch, potato starch or sodium carboxymethylcellulose; withlubricants, such as talc or magnesium stearate; and if desired, withdiluents, buffering agents, moistening agents, preservatives andflavoring agents. Such preparations can be used for oral administration.

A subject compound can be formulated into preparations for injection bydissolving, suspending or emulsifying the compound in an aqueous ornonaqueous solvent, such as vegetable or other similar oils, syntheticaliphatic acid glycerides, esters of higher aliphatic acids or propyleneglycol; and if desired, with conventional additives such assolubilizers, isotonic agents, suspending agents, emulsifying agents,stabilizers and preservatives. The preparation may also be emulsified orthe active ingredient encapsulated in liposome vehicles. Formulationssuitable for injection can be administered by an intravitreal,intraocular, intramuscular, subcutaneous, sublingual, or other route ofadministration, e.g., injection into the gum tissue or other oraltissue. Such formulations are also suitable for topical administration.

In some embodiments, a subject compound can be delivered by a continuousdelivery system. The term “continuous delivery system” is usedinterchangeably herein with “controlled delivery system” and encompassescontinuous (e.g., controlled) delivery devices (e.g., pumps) incombination with catheters, injection devices, and the like, a widevariety of which are known in the art.

A subject compound can be utilized in aerosol formulation to beadministered via inhalation. A subject compound can be formulated intopressurized acceptable propellants such as dichlorodifluoromethane,propane, nitrogen and the like.

Furthermore, a subject compound can be made into suppositories by mixingwith a variety of bases such as emulsifying bases or water-solublebases. A subject compound can be administered rectally via asuppository. The suppository can include vehicles such as cocoa butter,carbowaxes and polyethylene glycols, which melt at body temperature, yetare substantially solid at room temperature.

The term “unit dosage form,” as used herein, refers to physicallydiscrete units suitable as unitary dosages for human and animalsubjects, each unit containing a predetermined quantity of a subjectcompound calculated in an amount sufficient to produce the desiredeffect in association with a pharmaceutically acceptable diluent,carrier or vehicle. The specifications for a subject compound depend onthe particular compound employed and the effect to be achieved, and thepharmacodynamics associated with each compound in the host.

The dosage form of a disclosed pharmaceutical composition may bedetermined by the mode of administration chosen. For example, inaddition to injectable fluids, topical or oral dosage forms may beemployed. Topical preparations may include eye drops, ointments, spraysand the like. Oral formulations may be liquid (e.g., syrups, solutionsor suspensions), or solid (e.g., powders, pills, tablets, or capsules).Methods of preparing such dosage forms are known, or will be apparent,to those skilled in the art.

Certain embodiments of the pharmaceutical compositions that include asubject compound may be formulated in unit dosage form suitable forindividual administration of precise dosages. The amount of activeingredient administered may depend on the subject being treated, theseverity of the affliction, and the manner of administration, and isknown to those skilled in the art. In certain instances, the formulationto be administered contains a quantity of the compounds disclosed hereinin an amount effective to achieve the desired effect in the subjectbeing treated.

Each therapeutic compound can independently be in any dosage form, suchas those described herein, and can also be administered in various ways,as described herein. For example, the compounds may be formulatedtogether, in a single dosage unit (that is, combined together in oneform such as capsule, tablet, powder, or liquid, etc.) as a combinationproduct. Alternatively, when not formulated together in a single dosageunit, an individual subject compound may be administered at the sametime as another therapeutic compound or sequentially, in any orderthereof.

Methods of Administration

The subject compounds find use in the treatment of a disease ordisorder. Accordingly, the route of administration may be selectedaccording to a variety of factors including, but not limited to, thecondition to be treated, the formulation and/or device used, the patientto be treated, and the like. Routes of administration useful in thedisclosed methods include but are not limited to oral and parenteralroutes, such as intravenous (iv), intraperitoneal (ip), rectal, topical,ophthalmic, nasal, and transdermal. Formulations for these dosage formsare described herein.

An effective amount of a subject compound may depend, at least, on theparticular method of use, the subject being treated, the severity of theaffliction, and the manner of administration of the therapeuticcomposition. A “therapeutically effective amount” of a composition is aquantity of a specified compound sufficient to achieve a desired effectin a subject (e.g., patient) being treated. For example, this may be theamount of a subject compound necessary to treat (e.g., prevent, inhibit,reduce or relieve) a disease or disorder in a subject. In someinstances, a therapeutically effective amount of a compound is an amountsufficient to prevent, inhibit, reduce or relieve a disease or disorderin a subject without causing a substantial cytotoxic effect on hostcells.

Therapeutically effective doses of a subject compound or pharmaceuticalcomposition can be determined by one of skill in the art, with a goal ofachieving local (e.g., tissue) concentrations that are at least as highas the IC₅₀ of an applicable compound disclosed herein.

An example of a dosage range is from 0.1 to 200 mg/kg body weight orallyin single or divided doses. In some embodiments, a dosage range is from1.0 to 100 mg/kg body weight orally in single or divided doses,including from 1.0 to 50 mg/kg body weight, from 1.0 to 25 mg/kg bodyweight, from 1.0 to 10 mg/kg body weight (assuming an average bodyweight of approximately 70 kg; values may be adjusted accordingly forpersons weighing more or less than average). For oral administration,the compositions are, for example, provided in the form of a tabletcontaining from about 10 to about 1000 mg of the active ingredient, suchas 25 to 750 mg, or 50 to 500 mg, for example 75 mg, 100 mg, 200 mg, 250mg, 400 mg, 500 mg, 600 mg, 750 mg, or 1000 mg of the active ingredientfor the symptomatic adjustment of the dosage to the subject beingtreated. In certain embodiments of an oral dosage regimen, a tabletcontaining from 500 mg to 1000 mg active ingredient is administered once(e.g., a loading dose) followed by administration of ½ (i.e., half)dosage tablets (e.g., from 250 to 500 mg) each 6 to 24 hours for 3 daysor more.

The specific dose level and frequency of dosage for any particularsubject may be varied and may depend upon a variety of factors,including the activity of the subject compound, the metabolic stabilityand length of action of that compound, the age, body weight, generalhealth, sex and diet of the subject, mode and time of administration,rate of excretion, drug combination, and severity of the condition ofthe host undergoing therapy.

Embodiments of the present disclosure also include combinations of oneor more disclosed compounds with one or more other agents or therapiesuseful in the treatment of a disease or disorder. For example, one ormore disclosed compounds may be administered in combination withtherapeutically effective doses of other medicinal and pharmaceuticalagents, or in combination other non-medicinal therapies, such as hormoneor radiation therapy. The term “administration in combination with”refers to both concurrent and sequential administration of the activeagents.

Therapeutic Applications

The subject compounds are useful for treating a disease or disorder in asubject in need of treatment. Accordingly, the present disclosureprovides methods of treating a disease or disorder in a subject byadministering an amount (e.g., a therapeutically effective amount) of asubject compound, including a salt or solvate or stereoisomer thereof.

Embodiments of the present disclosure are also directed to a compound ofthe present disclosure or a salt or solvate or stereoisomer thereof, foruse in therapy or as a medicament. Additionally, embodiments aredirected to the use of a compound of the present disclosure or a salt orsolvate or stereoisomer thereof, for the manufacture of a medicament.The embodiments are also directed to the use of a compound of thepresent disclosure or a salt or solvate or stereoisomer thereof for themanufacture of a medicament for the treatment of a disease or disorder.

Diseases or conditions of interest for treatment according to thepresent disclosure include, but are not limited to, hypertension, cancer(e.g., lymphoma, such as cutaneous T cell lymphoma (CTCL), relapsed orrefractory peripheral T-cell lymphoma, etc.), multiple sclerosis (e.g.,relapsing-remitting multiple sclerosis), anemia (e.g., anemia in ChronicKidney Disease (CKD)), Irritable Bowel Syndrome (IBS; e.g., diarrheapredominant Irritable Bowel Syndrome (IBS-d)), cystic fibrosis, musculardystrophy (e.g., Duchenne muscular dystrophy), bacterial infections,cardiovascular disease (e.g., myocardial infarction, stroke, unstableangina, coronary heart disease, high blood pressure, congestive heartfailure, etc.), hyperlipidemia, diabetes, viral infections (e.g., HIV),liver disease (e.g., primary biliary cirrhosis, nonalcoholicsteatohepatitis (NASH), portal hypertension, bile acid diarrhea (bileacid malabsorption), etc.), inflammation, gout, inflammatory boweldisease (IBD), Crohn's disease, endometriosis, dyslipidemia (e.g.,hypercholesterolemia (heterozygous familial and nonfamilial) and mixeddyslipidemia (Fredrickson types IIa and IIb), heterozygous familialhypercholesterolemia, homozygous familial hypercholesterolemia,hypertriglyceridemia (Fredrickson Type IV), primarydysbetalipoproteinemia (Fredrickson Type III), combined hyperlipidemia,etc.), and the like.

Research Applications

Since subject compounds find use in the treatment of a disease ordisorder, such compounds are also useful as research tools. Accordingly,the disclosure also provides for a method for using a compound of thepresent disclosure or a salt or solvate or stereoisomer thereof as aresearch tool for studying a biological system or sample, or fordiscovering new chemical compounds.

The present disclosure also provides a method for using subjectcompounds as a research tool for studying a biological system or sample.For example, the disclosure provides for a method of studying abiological system or sample, the method including: (a) contacting thebiological sample with a compound of the present disclosure or a salt orsolvate or stereoisomer thereof; and (b) determining the effects causedby the compound on the biological sample.

Any suitable biological sample can be employed in such studies which canbe conducted either in vitro or in vivo. Representative biologicalsamples suitable for such studies include, but are not limited to,cells, cellular extracts, plasma membranes, tissue samples, isolatedorgans, mammals (such as mice, rats, guinea pigs, rabbits, dogs, pigs,humans, and so forth), and the like, with mammals being of particularinterest.

When used as a research tool, a biological sample is typically contactedwith an effective amount of a subject compound. After the biologicalsample is exposed to the compound, the effects of the compound aredetermined using conventional procedures and equipment, such as theassays disclosed herein. Exposure encompasses contacting the biologicalsample with the compound or administering the compound to a subject. Thedetermining step can involve measuring a response (a quantitativeanalysis) or can involve making an observation (a qualitative analysis).Measuring a response involves, for example, determining the effects ofthe compound on the biological sample using conventional procedures andequipment, such as radioligand binding assays and measuringligand-mediated changes in functional assays. The assay results can beused to determine the activity level as well as the amount of compoundnecessary to achieve the desired result.

Additionally, the subject compounds can be used as research tools forevaluating other chemical compounds, and thus are also useful inscreening assays to discover, for example, new compounds having asimilar activity. In this manner, a subject compound can be used as astandard in an assay to allow comparison of the results obtained with atest compound and with the subject compounds to identify those testcompounds that have about equal or superior activity, if any. Forexample, IC₅₀ data for a test compound or a group of test compounds iscompared to the IC₅₀ data for a subject compound to identify those testcompounds that have the desired properties, for example, test compoundshaving an IC₅₀ about equal or superior to a subject compound, if any.

This aspect includes, as separate embodiments, both the generation ofcomparison data (using the appropriate assays) and the analysis of testdata to identify test compounds of interest. Thus, a test compound canbe evaluated in a biological assay, by a method comprising the steps of:(a) conducting a biological assay with a test compound to provide afirst assay value; (b) conducting the biological assay with a subjectcompound to provide a second assay value; wherein step (a) is conductedeither before, after or concurrently with step (b); and (c) comparingthe first assay value from step (a) with the second assay value fromstep (b).

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the embodiments, and are not intended to limit the scope ofwhat the inventors regard as their invention nor are they intended torepresent that the experiments below are all or the only experimentsperformed. Efforts have been made to ensure accuracy with respect tonumbers used (e.g., amounts, temperature, etc.) but some experimentalerrors and deviations should be accounted for. As will be understood, bythose of skill in the art of organic synthesis and medicinal chemistrythe specific conditions set forth below are exemplary and can be variedor adapted to other reagents and products in routine fashion. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Celsius, andpressure is at or near atmospheric. Standard abbreviations may be used.

All reagents and solvents were purchased from commercial suppliers andused without further purification. Reactions were monitored bythin-layer chromatography or high-performance liquid chromatography. NMRwas performed on a 300 MHz NMR spectrometer and all chemical shifts arereported relative to a tetramethylsilane internal standard, or byreferencing on the deuterated solvent. Reverse-phase high-performanceliquid chromatography was performed on standard equipment and wascoupled to diode array and mass spectra detectors—the mass-spectradetector operating under the electrospray ionization (ESI) mode. Thecolumn-gradient system was as follows:

Column: Phenomenex Gemini 4.6×100 mm, C18, 5 μm, 110 Å

Column temperature 30° C.Sample temperature 15° C.Solvent A—0.05% Formic acid in WaterSolvent B—0.05% Formic acid in AcetonitrileFlow rate—1.5 mL/min

Gradient:

Time A % B % 0 95 5 10 0 100 (curve = 6) 11.1 0 100 11.2 95 5 12.1 95 5

High resolution mass spectrometry were obtained on a LCT Premier XE massspectrometer (time-of-flight) operating under the electrosprayionization mode. Mass analysis was performed in extended W-mode usingleucine enkephalin as reference lock mass (556.2771 Da for positive ion& 554.2615 Da for negative ion).

20 mL Vials with pressure-release caps were obtained from Chemglass(catalogue #CG-4912-05). Reactions could also be undertaken in parallelusing a heating block. The last position of the heating block was usedto house a vial containing heat-resistant silicone oil. A thermocouplewas then inserted in to the oil to control the temperature of the block.

Example 1

Experiments were performed to synthesize tetrazolones from acidchlorides using azidotrimethylsilane, which was used as both aco-reactant and solvent. The synthetic protocol minimized the formationof by-products, allowed for large-scale reactions, and provided productswhich contained a variety of functional groups, including the synthesisof tetrazolone analogs of active agents.

The general synthesis of tetrazolone derivatives is shown in Table 1.

TABLE 1 Reaction of 2-bromo-3-fluorobenzoyl chloride withazidotrimethylsilane.

Entry TMS—N₃ (equiv.) Yield of 4 (%) 1 6.0 82 2 4.5 76 3 3.0 37 44.0-6.0 (20-36 g scale) 80-94

An example of the synthesis of tetrazolones included the reaction of2-bromo-4-fluorobenzoyl chloride 3 with azidotrimethylsilane (TMS-N₃) at100° C. (Table 1). Reacting 3 (1.5 g) with 6.0 equiv. of TMS-N₃ producedtetrazolone 4 in 82% isolated yield (entry 1). Reducing thestoichiometry of TMS-N₃ led to significant formation of a symmetricalurea by-product, and a lower isolated yield of desired tetrazolone 4.For example, the use of 4.5 equivalents of TMS-N₃ gave a 76% yield oftetrazolone 4 (entry 2), while the use of 3.0 equivalents of TMS-N₃ gavea 37% yield of tetrazolone 4 (entry 3), together with large quantitiesof a symmetrical urea, 1,3-bis-(2-bromo-4-fluorophenyl)urea. The desiredtetrazolone 4 was obtained from all the above reaction mixtures bycooling, evaporation of the excess TMS-N₃ and use of abase/acidification extraction process to give product of high purity(>96%). The reaction was scaled-up without a significant decrease inyield. For instance, reactions with 20-36 g of acid chloride 3 and4.0-6.0 equivalents of TMS-N₃ resulted in a 80-94% isolated yields oftetrazolone 4 (entry 4).

Reactions were performed using at least 6.0 equivalents of neat TMS-N₃with a variety of different acid chloride substrates. In order todemonstrate that tetrazolone formation could be undertaken in a parallelmanner, some reactions were performed in sealed vials with apressure-release cap. Multiple reactions could be performed in a singleheating block. After completion of the reaction, the mixture wasworked-up by evaporating the excess TMS-N₃, extracting using a base/acidprotocol, then purifying further with silica gel chromatography, ifneeded. The results of these experiments are shown in Table 2. As shownin Table 2, the reaction was useful for a variety of differentfunctionalities in the acid chloride. For example, alkyl,trifluoromethyl, aryl, heteroaryl, alkenyl, nitro, fluoro, chloro,bromo, iodo, ketone, nitrile, pentafluorosulfanyl, ether, thioether,ester, amide and sulfonamide groups remained intact under the reactionconditions (entries 1-21). Additionally, reactions of acid chloridesdirectly attached to heteroaryl, alkenyl, or alkyl moieties were alsosuccessful (entries 22-26).

As shown in Table 2, reactions of acid chlorides containingtrifluoromethyl- or fluoro-groups were successful (entries 4, 6 and 7).In addition, groups prone to nucleophilic aromatic displacement, such asactivated halides, remained intact under the reaction conditions(entries 6, 7, 9-10). The efficiency of the reaction was unaffected bythe presence of large ortho-substituents (entries 9-11), such as in areaction to produce a tetrazolone analog of the herbicide 2,4-D (entry11). The reaction of an acid chloride containing a ketone group did notproduce concomitant Schmidt reaction (entry 12). Similarly,azidotrimethylsilane did not react with a substrate containing a nitrilegroup (entry 13). As shown in Table 2, the reaction of an acid chloridecontaining a pentafluorosulfanyl substituent also resulted in productionof the desired tetrazolone derivative (entry 14).

In addition, reactions were performed to form a tetrazolone in afinal-step, from fully-functionalized active agents, where a tetrazolonegroup served as a carboxylic acid bioisostere. For example, atetrazolone derivative of Aspirin was produced and gave a 56% isolatedyield of the tetrazolone product (entry 17). Tetrazolone analogs of theactive agents Indomethacin, Probenecid, Telmisartan and Bexarotene werealso prepared (entries 18-21). Isolated yields were 33-89%. Reactionswith hetroaroyl chlorides were also performed. Both electron-deficientsix-membered heterocycles (entry 22), and electron-rich five-memberedheterocycles (entries 23 and 24) formed tetrazolone products under thereaction conditions. Compound 6v (entry 22) was a direct tetrazoloneanalog of the active agent Niacin. Reaction of acid chlorides attachedto an olefin, or alkane (entries 25 and 26) were also performed. Thereaction of hemi-fumarate 5y, gave a 62% yield of tetrazolone 6y (entry25). The reaction with an acid chloride attached to an alkane, such aspropionyl chloride 5z, afforded ethyl-tetrazolone 6z, in a 14% yieldunder the reaction conditions (entry 26; compare also with entries 11and 18).

TABLE 2 Tetrazolone formation with acid chlorides andazidotrimethylsilane.

Entry Starting Material Product Yield (%) 1

76  2

66  3

61  4

56  5

90  6

70  7

86  8

60  9

76  10

66  11

43^(a) 12

59^(a) 13

90  14

65^(a) 15

73^(a) 16

20  17

56  18

82^(a) 19

68^(a) 20

33^(a) 21

89^(a) 22

65  23

30  24

86  25

62^(a) 26

14  ^(a)Acid chloride was prepared from acid prior to reaction withazidotrimethylsilane - reported yield is from acid to tetrazolone.

Preparation of 1-(2-bromo-4-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one4

Table 1, entry 1: Azidotrimethyisilane (5 mL, 38.0 mmol) was added inone portion to 2-bromo-4-fluorobenzoyl chloride 3 (1.5 g, 6.3 mmol). Themixture was placed under nitrogen and then heated to 100° C. withstirring [Note: 100° C. refers to temperature of heating block]. Themixture was left to stir at 100° C. overnight. After cooling, themixture was concentrated under vacuum and the residue partitionedbetween EtOAc (50 mL) and H₂O (50 mL). The organic layer was thenextracted with a saturated aqueous solution of NaHCO₃ (4×40 mL) [Note:extraction continued until TLC showed all tetrazolone product removedfrom the organic layer]. EtOAc (50 mL.) was added to the combined NaHCO₃layers, and the pH was adjusted to <3 using 6N HCl with efficientstirring. The aqueous and organic layers were partitioned, and theaqueous layer extracted with EtOAc (1×50 mL). The combined organiclayers were dried (MgSO₄), filtered and the solvent removed under vacuumto afford the product (1.34 g, 82%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.90 (dd, J=8.4, 2.7 Hz, 1H), 7.77 (dd,J=8.7, 5.7 Hz, 1H), 7.52-7.45 (m, 1H), −1.2 (br. s, 1H)

¹⁹F NMR (DMSO-d₆, MHz): −107.6 (dd, J=13.8, 7.6 Hz)

¹³C NMR (DMSO-d₆, 75 MHz): δ 164.2 (d, J=251 Hz), 150.7, 132.0 (d, J=9.3Hz), 128.7 (d, J=3.8 Hz), 122.6 (d, J=11.0 Hz), 121.0 (d, J=26 Hz),116.4 (d, J=23 Hz) m/z=257.28 [M−H]⁺ for ⁷⁹Br

HRMS (EI): [M−H]⁺ calc'd for C₇H₄BrFN₄O m/z 256.9474, found 256.9527.

Table 1, entry 2: The above reaction was repeated using 4.5 equivalentsof azidotrimethylsilane (3.75 mL) to give the product (1.24 g, 76%) as asolid.

Table 1, entry 3: The above reaction was repeated using 3.0 equivalentsof azidotrimethylsilane (2.5 mL) to give the product (0.6 g, 37%) as asolid. Also isolated from the EtOAc layer after extraction withsaturated NaHCO₃ was a symmetrical urea by-product,bis-(2-bromo-4-fluorphenyl)urea.

Data for bis-(2-bromo-4-fluorphenyl)urea:

¹H NMR (DMSO-d₆, 300 MHz): δ 8.82 (br. s, 2H), 7.88 (dd, J=9.0, 5.7 Hz,2H), 7.57 (dd, J=8.7, 3.0 Hz, 2H), 7.22 (ddd, J=9.0, 8.1, 3.0, Hz, 21H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 159.2 (d, J=244 Hz), 152.7, 133.7 (d, J=3.3Hz), 125.1 (d, J=8.3 Hz), 119.4 (d, J=25 Hz), 115.0 (d, J=22 Hz), 114.8(d, J=10 Hz)

m/z=407.26 [M+H]⁺ and 405.37 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₁₃H₈Br₂F₂N₂O m/z 404.9050, found 404.9047;m/z 406.9030, found 406.9025; m/z 408.9011, found 408.9003.

HRMS (EI): [M−H]⁺ calc'd for C₁₃H₈Br₂F₂N₂O m/z 402.8893, found 402.8912;m/z 404.8873, found 404.8815; m/z 406.8854, found 406.8802.

Table 1, entry 4: Note: For large-scale reactions, the mixtures wereonly placed under a nitrogen atmosphere after cessation of the gasevolution. The above reaction was repeated on a large-scale usingazidotrimethylsilane (65 mL, 494 mmol) and 2-bromo-4-fluorobenzoylchloride 3 (20.4 g, 85.9 mmol). The mixture was heated slowly andevolution of a gas (presumably, arising from a Curtius rearrangement)was noted from 50-60° C. (block temperature), which became a vigorousevolution when the block temperature was raised to ca. 65° C. Themixture was removed from the heat at a block temperature of ca. 70° C.,and when gas evolution subsided, was re-subjected to heating stepwisefrom ca. 70° C. to 90° C. The mixture was stirred at 90° C.: overnight.Usual workup, partitioning between EtOAc (200 mL) and H₂O (100 mL) andthen extracting the organic layer with a saturated solution of NaHCO₃(5×150 mL), followed by acidification and extraction with EtOAc, gavethe product (19.9 g, 89%) as a solid.

A separate reaction using 20.0 g of ²-bromo-4-fluorobenzoyl chloride 3and 47 mL of azidotrimethylsilane (4.0 equivalents) gave the product(17.4 g, 80%) as a solid.

A separate reaction using 36 g of 2-bromo-4-fluorobenzoyl chloride 3 and120 mL of azidotrimethylsilane (6.0 equivalents) gave the product (37 g,94%) as a solid. For this reaction, the mixture was heated slowly to ca.55° C., whereupon the evolution of gas became regular. Evolution of gasstopped after ca. 15 min at 55° C. The mixture was then slowly heated to90-95° C. (block temperature), placed under a nitrogen atmosphere andstirred overnight.

Preparation of 1-(2-bromo-4-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one4 from 2-bromo-4-fluoro-1-isocyanoatobenzene

Azidotrimethylsilane (10 mL, 76 mmol) was added in one portion to2-bromo-4-fluoro-1-isocyanatobenzene (3.0 g, 13.9 mmol). The mixture wasplaced under nitrogen and then heated to 90° C. with stirring [Note: 90°C. refers to temperature of heating block]. The mixture was left to stirat 90° C. overnight. After cooling, the mixture was concentrated undervacuum and the residue partitioned between EtOAc (50 mL) and a saturatedaqueous solution of NaHCO₃ (100 mL). The organic layer was extractedwith a further quantity of saturated aqueous NaHCO₃ (1×50 mL). EtOAc(100 mL) was added to the combined NaHCO₃ layers, and the pH wasadjusted to <3 using 2N HCl with efficient stirring. The aqueous andorganic layers were partitioned, and the organic layer was dried(Na₂SO₄), filtered and the solvent removed under vacuum to afford theproduct (3.44 g, 95%) as a solid.

A separate reaction was performed using 20.0 g of2-bromo-4-fluoro-1-isocyanatobenzene (92.6 mmol) and 50 mL ofazidotrimethylsilane (380 mmol; ca. 4.0 equivalents) to give the product(20.1 g, 84%) after workup.

Experiments with related starting materials indicated that theisocyanate to tetrazolone formation was complete within ca. 2 hours. Itwas likely that the reaction of acid chlorides to tetrazolones wassimilarly complete within a few hours, since it was observed that theCurtius rearrangement occurred quickly (evolution of gas complete within15-30 min). In some instances, the reactions were typically runovernight for convenience.

Preparation of 1-phenyl-1,4-dihydro-5H-tetrazol-5-one 6a

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and benzoylchloride (422 mg, 3.0 mmol) was heated from room temperature to 100° C.(block temperature) in a sealed vial with pressure-release cap. Themixture was then stirred at 100° C. overnight (Note: pressure developedduring heating). After cooling, the mixture was concentrated undervacuum and the residue partitioned between EtOAc (10 mL) and a saturatedaqueous solution of NaHCO₃ (10 mL). The organic layer was extracted witha further quantity of saturated aqueous NaHCO₃ (1×10 mL) [note: organiclayer assessed by TLC to ascertain if tetrazolone product was completelyremoved. If tetrazolone was still present in organic layer, then furtherextractions with saturated NaHCO₃ were used]. EtOAc (20 mL) was added tothe combined NaHCO₃ layers, and the pH was adjusted to <3 using 6N HClwith efficient stirring. The aqueous and organic layers were partitionedand the aqueous layer was extracted with EtOAc (2×10 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and the solvent removedunder vacuum to afford the product (369 mg, 76%) as a solid. A samplewas recrystallized from EtOAc.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.85-7.81 (m, 2H), 7.57-7.50 (m, 2H), 7.41(dt, J=7.5, 1.5 Hz, 1H), −1.3 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.3, 134.2, 129.5, 127.6, 119.5

m/z 163.18 [M+H]⁺ and 161.24 [M−H]⁺.

HRMS (EI): [M−H]⁺ calc'd for C₇H₆N₄O m/z 161.0463, found 161.0532.

Preparation of 1-(naphthalen-2-yl)-1,4-dihydro-5H-tetrazol-5-one 6b

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and2-naphthoyl chloride (572 mg, 3.0 mmol) was heated from room temperatureto 100° C. (block temperature) in a sealed vial with pressure-releasecap. The mixture was then stirred at 100° C. overnight (Note: pressuredeveloped during heating). After cooling, the mixture was concentratedunder vacuum and the residue partitioned between EtOAc (10 mL) and asaturated aqueous solution of NaHCO₃ (10 mL). The organic layer wasextracted with a further quantity of saturated aqueous NaHCO₃ (1×10 mL)[note: organic layer was assessed by TLC to ascertain if tetrazoloneproduct was completely removed. If tetrazolone was still present inorganic layer, then further extractions with saturated NaHCO₃ wereused]. EtOAc (20 mL) was added to the combined NaHCO₃ layers, and the pHwas adjusted to <3 using 6N HCl with efficient stirring. The aqueous andorganic layers were partitioned and the aqueous layer was extracted withEtOAc (2×10 mL). The combined organic layers were dried (Na₂SO₄),filtered and the solvent removed under vacuum to afford the product (419mg, 66%) as a solid. A sample was recrystallized from EtOAc.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.42 (d, J=2.1 Hz, 1H), 8.09 (d, J=8.7 Hz,1H), 8.02-7.93 (m, 3H), 7.60-7.52 (m, 2H), −1.1 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.4, 132.7, 131.8, 131.6, 129.5, 128.1,127.8, 127.2, 126.6, 118.1, 117.0

m/z=216.36 [M+H]⁺ and 215.45 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₁₁H₈N₄O m/z 213.0776, found 213.0764.

Preparation of 1-(4-(tert-butyl)phenyl)-1,4-dihydro-5H-tetrazol-5-one 6C

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and4-(tert-butyl)benzoyl chloride (590 mg, 3.0 mmol) was heated from roomtemperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. overnight(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and the residue partitioned between EtOAc(20 mL) and a saturated aqueous solution of NaHCO₃ (20 mL). The organiclayer was extracted with a further quantity of saturated aqueous NaHCO₃(10×15 mL) [note: organic layer was assessed by TLC to ascertain iftetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (40 mL) was added to the combined NaHCO₃ layers, andthe pH was adjusted to <3 using 6N HCl with efficient stirring. Theaqueous and organic layers were partitioned and the aqueous layer wasextracted with EtOAc (2×40 mL). The combined organic layers were dried(Na₂SO₄), filtered and the solvent removed under vacuum to afford theproduct (401 mg, 61%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.74 (dt, J=8.7, 2.4 Hz, 2H), 7.57 (dt,J=8.7, 2.4 Hz, 2H), 1.29 (s, 9H), −1.3 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.3, 139.0, 131.7, 126.2, 119.5, 34.4,31.0

m/z=219.31[M+H]+ and 217.38 [M−H]⁺

HRMS (EI): [M−H]⁺ calc'd for C₁₁H₁₄N₄O m/z 217.1089, found 213.1139.

Preparation of1-(3,5-bis(trifluoromethyl)phenyl)-1,4-dihydro-5H-tetrazol-5-one 6d

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and3,5-bis(trifluoromethyl)benzoyl chloride (830 mg, 3.0 mmol) was heatedfrom room temperature to 100° C. (block temperature) in a sealed vialwith pressure-release cap. The mixture was then stirred at 100° C.overnight (Note: pressure developed during heating). After cooling, themixture was concentrated under vacuum and the residue partitionedbetween EtOAc (10 mL) and a saturated aqueous solution of NaHCO₃ (10mL). The organic layer from the initial partition above was concentratedunder vacuum and purified by column chromatography on silica gel usinghexane/EtOAc as eluent (ISCO Combiflash System) to give the product (503mg, 56%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.48 (s, 2H), 8.14 (s, 1H), −1.2 (br. s,1H)

¹⁹F NMR (DMSO-d₆, 282 MHz): δ −61.8 (s)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.4, 136.0, 131.7 (q, J=33 Hz), 124.6 (q,J=271 Hz), 120.6 (m), 118.9 (m)

m/z=297.36 [M−H]⁺

HRMS (EI): [M−H]⁺ calc'd for C₉H₄F₆N₄O m/z 297.0211, found 297.0157.

Preparation of 1-(3-nitrophenyl)-1,4-dihydro-5H-tetrazol-5-one 6e

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and3-nitrobenzoyl chloride (554 mg, 3.0 mmol) was heated from roomtemperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. for 2 hr(Note: pressure develops during heating). After cooling, the mixture wasconcentrated under vacuum and the residue partitioned between EtOAc (10mL) and a saturated aqueous solution of NaHCO₃ (10 mL). The organiclayer was extracted with a further quantity of saturated aqueous NaHCO₃(1×10 mL) [note: organic layer was assessed by TLC to ascertain iftetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (20 mL) was added to the combined NaHCO₃ layers, andthe pH was adjusted to <3 using 6N HCl with efficient stirring. Theaqueous and organic layers were partitioned and the aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic layers were dried(Na₂SO₄), filtered and the solvent removed under vacuum to afford theproduct (560 mg, 90%) as a solid. A sample was recrystallized fromEtOAc.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.69 (t, J=4.2 Hz, 1H), 8.28-8.19 (m, 2H),7.82 (t, J=8.3 Hz, 1H), −1.0 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.1, 148.1, 135.1, 131.2, 124.8, 121.8,113.2

m/z=208.25 [M+H]⁺ and 206.30 [M−H]⁺

HRMS (EI): [M−H]⁺ calc'd for C₇H₅N₅O₃ m/z 206.0314, found 206.0398.

Preparation of 1-(4-fluoro-5-nitrophenyl)-1,4-dihydro-5H-tetrazol-5-one6f

A stirred mixture of azidotrimethylsilane (7.9 mL, 60 mmol) and4-fluoro-5-nitrobenzoyl chloride (2.04 g, 10 mmol) in a round bottomflask with reflux condenser was heated slowly from room temperature to90° C. under an atmosphere of nitrogen (block temperature). The mixturewas then stirred at 90° C. overnight. After cooling, the mixture wasconcentrated under vacuum and the residue partitioned between EtOAc (50mL) and H₂O (50 mL). The organic layer was extracted with a saturatedaqueous solution of NaHCO₃ (3×50 mL) [note: organic layer was assessedby TLC to ascertain if tetrazolone product was completely removed. Iftetrazolone was still present in organic layer, then further extractionswith saturated NaHCO₃ were used]. EtOAc (100 mL) was added to thecombined NaHCO₃ layers, and the pH was adjusted to <3 using 6N HCl withefficient stirring. The aqueous and organic layers were partitioned andthe organic layer was dried (MgSO₄), filtered and the solvent removedunder vacuum to afford the product (1.96 g) as a solid. ¹H NMR analysisindicated that the product was ca. 80-90% purity with approximately10-20% of 4-fluoro-3-nitrobenzoic acid as a contaminant. Adjusting theyield for purity gives ca. 70% of desired product.

A sample of the above material was recrystallized from EtOAc to providepure material.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.63 (dd, J=9.6, 2.7 Hz, 1H), 8.25 (ddd,J=9.3, 3.9, 2.7 Hz, 1H), 7.80 (dd, J=11.1, 9.0 Hz, 1H), −1.0 (br. s, 1H)

¹⁹F NMR (DMSO-d₆, 272 MHz): δ −119.7 (m)

¹³C NMR (DMSO-d₆, 75 MHz): δ 154.9 (d, J=261 Hz), 150.2, 136.9 (d, J=8Hz), 130.6 (d, J=3 Hz), 127.0 (d, J=9 Hz), 120.1 (d, J=23 Hz), 116.6 (d,J=3 Hz)

m/z=226.24 [M+H]⁺ and 224.32 [M−H]⁺

HRMS (EI): [M−H]⁺ calc'd for C₇H₄FN₅O₃ m/z 224.0220, found 224.0227.

Preparation of 1-(2-fluoro-5-nitrophenyl)-1,4-dihydro-5H-tetrazol-5-one6g

A stirred mixture of azidotrimethylsilane (19.7 mL, 150 mmol) and2-fluoro-5-nitrobenzoyl chloride (5.1 g, 25 mmol) in a round bottomflask with reflux condenser was heated slowly from room temperature to90° C. (block temperature) (note: evolution of nitrogen was observedfrom 70° C.). The mixture was then stirred at 90° C. for 5-6 hr (TLCindicated complete reaction). After cooling, the mixture wasconcentrated under vacuum and the residue partitioned between EtOAc (100mL) and a saturated aqueous solution of NaHCO₃ (150 mL). The organiclayer was extracted with a further quantity of saturated aqueous NaHCO₃(1×50 mL) [note: organic layer was assessed by TLC to ascertain iftetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (200 mL) was added to the combined NaHCO₃ layers, andthe pH was adjusted to <3 using 6N HCl with efficient stirring. Theaqueous and organic layers were partitioned and the aqueous layer wasextracted with EtOAc (1×100 mL). The combined organic layers were dried(MgSO₄), filtered and the solvent removed under vacuum to afford theproduct (4.8 g, 86%) as a solid. A sample was recrystallized from EtOAc.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.66-8.63 (m, 1H), 8.49-8.43 (m, 1H), 7.82(t, J=7.5 Hz, 1H), −1.0 (br. s, 1H)

¹⁹F NMR (DMSO-d₆, 272 MHz): δ −110.4 (m)

¹³C NMR (DMSO-d₆, 75 MHz): δ 160.9 (d, J=262 Hz), 150.5, 144.0 (d, J=3.1Hz), 127.2 (d, J=9.9 Hz), 123.4 (d, J=2.2 Hz), 121.6 (d, J=13.7 Hz),118.7 (d, J=22.1 Hz)

m/z=226.24 [M+H]⁺ and 224.30 [M−H]⁺

HRMS (EI): [M−H]⁺ calc'd for C₇H₄FN₅O₃ m/z 224.0220, found 224.0231.

Preparation of 1-(3-chlorophenyl)-1,4-dihydro-5H-tetrazol-5-one 6h

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and3-chlorobenzoyl chloride (525 mg, 3.0 mmol) was heated from roomtemperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. overnight(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and the residue partitioned between EtOAc(10 mL) and a saturated aqueous solution of NaHCO₃ (10 mL). The organiclayer was extracted with a further quantity of saturated aqueous NaHCO₃(1×10 mL) [note: organic layer was assessed by TLC to ascertain iftetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (20 mL) was added to the combined NaHCO₃ layers, andthe pH was adjusted to <3 using 6N HCl with efficient stirring. Theaqueous and organic layers were partitioned and the aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic layers were dried(Na₂SO₄), filtered and the solvent removed under vacuum to afford theproduct (355 mg, 60%) as a solid. A sample was recrystallized fromEtOAc.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.92 (t, J=2.1 Hz, 1H), 7.82 (ddd, J=8.2,2.1, 1.2 Hz, 1H), 7.59 (t, J=8.3 Hz, 1H), 7.46 (ddd, J=8.1, 2.1, 0.9 Hz,1H), −1.1 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.1, 135.4, 133.7, 131.3, 127.3, 118.7,117.6

m/z=197.30 [M+H]⁺ and 195.38 [M−H]⁺ for ³⁵Cl

HRMS (EI): [M+H]⁺ calc'd for C₇H₅ClN₄O m/z 195.0074, found 195.0099.

Preparation of 1-(2-bromophenyl)-1,4-dihydro-5H-tetrazol-5-one 6i

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and2-bromobenzoyl chloride (590 mg, 3.0 mmol) was heated from roomtemperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. for 24 hr(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and the residue partitioned between EtOAc(20 mL) and a saturated aqueous solution of NaHCO₃ (20 mL). The organiclayer was extracted with a further quantity of saturated aqueous NaHCO₃(1×20 mL) [note: organic layer was assessed by TLC to ascertain iftetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (30 mL) was added to the combined NaHCO₃ layers, andthe pH was adjusted to <3 using 6N HCl with efficient stirring. Theaqueous and organic layers were partitioned and the aqueous layer wasextracted with EtOAc (2×30 mL). The combined organic layers were dried(Na₂SO₄), filtered and the solvent removed under vacuum to afford theproduct (546 mg, 76%) as a solid. A sample was recrystallized fromEtOAc.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.89 (dd, J=8.1, 1.5 Hz, 1H), 7.68 (dd,J=7.8, 2.1 Hz, 1H),

7.61-7.50 (m, 2H), −1.3 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.7, 133.5, 132.4, 131.9, 130.3, 129.0,121.3

m/z=239.24 [M−H]⁺

HRMS (EI): [M−H]⁺ calc'd for C₇H₅BrN₄O m/z 238.9568, found 238.9577.

Preparation of 1-(2-iodophenyl)-1,4-dihydro-5H-tetrazol-5-one 6j

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and2-iodobenzoyl chloride (799 mg, 3.0 mmol) was heated from roomtemperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. overnight(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and the residue partitioned between EtOAc(10 mL) and a saturated aqueous solution of NaHCO₃ (10 mL). The organiclayer was extracted with a further quantity of saturated aqueous NaHCO₃(1×10 mL) [note: organic layer was assessed by TLC to ascertain iftetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (20 mL) was added to the combined NaHCO₃ layers, andthe pH was adjusted to <3 using 6N HCl with efficient stirring. Theaqueous and organic layers were partitioned and the aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic layers were dried(Na₂SO₄), filtered and the solvent removed under vacuum to afford theproduct (567 mg, 66%) as a solid. A sample was recrystallized fromEtOAc.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.07 (m, 1H), 7.61-7.57 (m, 2H), 7.38-7.29(m, 1H), −1.3 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.5, 139.6, 135.5, 132.3, 129.6, 129.6,98.2

m/z=289.31 [M+H]⁺ and 287.42 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₇H₅IN₄O m/z 289.9586, found 289.9588.

Preparation of1-((2,4-dichlorophenoxy)methyl)-1,4-dihydro-5H-tetrazol-5-one 6k

Oxalyl chloride (2.0 M in CH₂Cl₂; 3.0 mL, 6.0 mmol) was added dropwiseover 2-3 min to a stirred suspension of 2,4-dichlorophenoxyacetic acid,also known as 2,4-D (663 mg, 3.0 mmol) and DMF (1-2 drops) in CH₂Cl₂ (6mL) at 0° C. under nitrogen. After complete addition, the mixture wasallowed to warm to room temperature and stirred over a weekend (note: asolution developed after warming to rt). The mixture was concentratedunder vacuum to leave the acid chloride 5k, which was used directly inthe tetrazolone-forming step below (yield assumed quantitative=718 mg).

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and2,4-dichlorophenoxyacetyl chloride (718 mg, 3.0 mmol) was heated fromroom temperature to 100° C. (block temperature) in a round bottom flaskwith reflux condenser under an atmosphere of nitrogen. The mixture wasthen stirred at 100° C. for 3 hours. After cooling, the mixture wasconcentrated under vacuum and the residue partitioned between EtOAc (30mL) and a saturated solution of NaHCO₃ (30 mL). The organic layer wasextracted with a saturated solution of NaHCO₃ (1×30 mL) [note: organiclayer was assessed by TLC to ascertain if tetrazolone product wascompletely removed. If tetrazolone was still present in organic layer,then further extractions with saturated NaHCO₃ were used]. EtOAc (30 mL)was added to the filtrate and the pH was adjusted to <3 using 6N HClwith efficient stirring. The aqueous and organic layers were partitionedand the aqueous layer was extracted with EtOAc (2×20 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and the solvent removedunder vacuum to afford the crude product (600 mg) of ca. 90% purity. Thecrude product was purified by column chromatography on silica gel (ISCOCombiflash) using CH₂Cl₂/MeOH (1:0 to 9:1) as eluent to give pureproduct (336 mg, 43%) as a solid. Less pure product (ca. 130 mg) wasalso obtained from the column, but was not purified further.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.59 (d, J=2.4 Hz, 1H), 7.49 (d, J=8.7 Hz,1H), 7.43 (dd, J=8.7, 2.4 Hz, 1H), 5.94 (s, 2H), −1.4 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 151.3, 150.6, 129.7, 128.3, 127.2, 124.2,118.6, 71.2

m/z=261.30 [M+H]⁺ and 259.37 [M−H]⁺ for ³⁵Cl

Preparation of 1-(4-acetylphenyl)-1,4-dihydro-5H-tetrazol-5-one 6l

Oxalyl chloride (2.0 M in CH₂Cl₂; 3.0 mL, 6.0 mmol) was added dropwiseover 2-3 min to a stirred suspension of 4-acetylbenzoic acid (493 mg,3.0 mmol) and DMF (1-2 drops) in CH₂Cl₂ (6 mL) at 0° C. under nitrogen.After complete addition, the mixture was allowed to warm to roomtemperature and stirred overnight. The mixture was concentrated undervacuum to leave the acid chloride 5l, which was used directly in thetetrazolone-forming step below (yield assumed quantitative=548 mg).

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and4-acetylbenzoyl chloride (548 mg, 3.0 mmol) was heated from roomtemperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. overnight(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and the residue partitioned between EtOAc(100 mL) and a 1:1 mixture of saturated NaHCO₃ (75 mL) and H₂O (75 mL).The organic layer was extracted with a 1:1 mixture of saturated NaHCO₃(25 mL) and H₂O (25 mL) [note: organic layer was assessed by TLC toascertain if tetrazolone product was completely removed. If tetrazolonewas still present in organic layer, then further extractions withsaturated NaHCO₃ were used]. The aqueous layer was filtered to removeminor insoluble items and then EtOAc (100 mL) was added to the filtrate.The pH was adjusted to <3 using 6N HCl with efficient stirring (if anazidohydrin was formed from the reaction, then treatment with acid mayrelease HCN). The aqueous and organic layers were partitioned and theaqueous layer was extracted with EtOAc (2×75 mL). The combined organiclayers were dried (Na₂SO₄), filtered and the solvent removed undervacuum to afford the crude product (445 mg) of ca. 90-95% purity. Thecrude product was purified by column chromatography on silica gel (ISCOCombiflash) using CH₂Cl₂/MeOH (1:0 to 9:1) as eluent to give the product(360 mg, 59%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.11 (d, J=7.2 Hz, 2H), 8.02 (d, J=9.0 Hz,2H), 2.58 (s, 3H), −1.0 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 196.8, 150.1, 137.8, 135.1, 129.7, 118.3,26.7

m/z=203.30 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₉H₈N₄O₂ m/z 205.0726, found 205.0721.

Preparation of 1-(3-cyanophenyl)-1,4-dihydro-5H-tetrazol-5-one 6m

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and3-cyanobenzoyl chloride (497 mg, 3.0 mmol) was heated from roomtemperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. overnight(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and the residue partitioned between EtOAc(10 mL) and a saturated aqueous solution of NaHCO₃ (10 mL). The organiclayer was extracted with a further quantity of saturated aqueous NaHCO₃(1×10 mL) [note: organic layer was assessed by TLC to ascertain iftetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (20 mL) was added to the combined NaHCO₃ layers, andthe pH was adjusted to <3 using 6N HCl with efficient stirring. Theaqueous and organic layers were partitioned and the aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic layers were dried(Na₂SO₄), filtered and the solvent removed under vacuum to afford theproduct (505 mg, 90%) as a solid. A sample was recrystallized fromEtOAc.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.26 (m, 1H), 8.16 (ddd, J=8.7, 2.4, 1.2Hz, 1H), 7.87 (dt, J=7.8, 2.7 Hz, 1H), 7.48 (dt, J=8.3, 0.6 Hz, 1H),−1.1 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.1, 134.9, 131.1, 131.0, 123.7, 122.1,117.9, 112.4

m/z=188.30 [M+H]⁺ and 186.42 [M−H]⁺

HRMS (EI): [M−H]⁺ calc'd for C₈H₅N₅O m/z 186.0486, found 186.0427.

Preparation of1-(3-(pentafluorosulfanyl)phenyl)-1,4-dihydro-5H-tetrazol-5-one 6n

Oxalyl chloride (2.0 M in CH₂Cl₂; 0.75 mL, 1.5 mmol) was added dropwiseover 2-3 min to a stirred suspension of 3-(pentafluorosulfanyl)benzoicacid (248 mg, 1.0 mmol) and DMF (2-3 drops) in CH₂Cl₂ (3 mL) at 0° C.under nitrogen. After complete addition, the mixture was stirred at 0°C. for 1 hr then allowed to warm to room temperature and stirred for 3hr. The mixture was concentrated under vacuum to leave the acid chloride5n, which was used directly in the tetrazolone-forming step below (yieldassumed quantitative=267 mg).

Note: 18 equivalent of TMS-N₃ were used in order to ensure completecoverage of the material in a vial with pressure-release cap.

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and3-(pentafluorosulfanyl)benzoyl chloride (267 mg, 1.0 mmol) was heatedfrom room temperature to 100° C. (block temperature) in a sealed vialwith pressure-release cap. The mixture was then stirred at 100° C.overnight (Note: pressure developed during heating). After cooling, themixture was concentrated under vacuum and the residue partitionedbetween EtOAc (20 mL) and a saturated aqueous solution of NaHCO₃ (10mL). The organic layer was extracted with a further quantity ofsaturated aqueous NaHCO₃ (8×10 mL) [note: organic layer was assessed byTLC to ascertain if tetrazolone product was completely removed. Iftetrazolone was still present in organic layer, then further extractionswith saturated NaHCO₃ were used]. EtOAc (30 mL) was added to thecombined NaHCO₃ layers, and the pH was adjusted to <3 using 6N HCl withefficient stirring. The aqueous and organic layers were partitioned andthe aqueous layer was extracted with EtOAc (2×30 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and the solvent removedunder vacuum to afford the product (187 mg, 65%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.40 (t, J=2.1 Hz, 1H), 8.14 (d, J=8.1 Hz,1H), 7.92-7.96 (m, 1H), 7.80 (t, J=8.6 Hz, 1H), −1.1 (br. s, 1H)

¹⁹F NMR (DMSO-d₆, 272 MHz): δ −114.4 (quin., J=145 Hz), −136.2 (d, J=145Hz)

¹³C NMR (DMSO-d₆, 75 MHz): δ 153.0 (quin., J=17.3 Hz), 150.2, 134.7,130.9, 124.5 (quin., J=4.7 Hz), 123.0, 116.1 (quin., J=5.0 Hz)

m/z=287.45 [M−H]⁺

HRMS (EI): [M−H]⁺ calc'd for C₇H₅F₃N₄OS m/z 287.0026, found 287.0059.

Preparation of 1-(4-(methylthio)phenyl)-1,4-dihydro-5H-tetrazol-5-one 6o

Oxalyl chloride (2.0 M in CH₂Cl₂; 3.0 mL, 6.0 mmol) was added dropwiseover 2-3 min to a stirred suspension of 4-(methylthio)benzoic acid (505mg, 3.0 mmol) and DMF (1-2 drops) in CH₂Cl₂ (6 mL) at 0° C. undernitrogen. After complete addition, the mixture was allowed to warm toroom temperature and stirred overnight. The mixture was concentratedunder vacuum to leave the acid chloride 5o, which was used directly inthe tetrazolone-forming step below (yield assumed quantitative=560 mg).

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and4-(methylthio)benzoyl chloride (560 mg, 3.0 mmol) was heated from roomtemperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. overnight(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and the residue partitioned between EtOAc(100 mL) and a 1:1 mixture of saturated NaHCO₃ (50 mL) and H₂O (50 mL).The organic layer was extracted with a further quantity of saturatedaqueous NaHCO₃ (2×30 mL) [note: organic layer was assessed by TLC toascertain if tetrazolone product was completely removed. If tetrazolonewas still present in organic layer, then further extractions withsaturated NaHCO₃ were used]. EtOAc (75 mL) was added to the combinedNaHCO₃ layers, and the pH was carefully adjusted to <3 using 6N HCl withefficient stirring. The aqueous and organic layers were partitioned andthe aqueous layer was extracted with EtOAc (2×50 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and the solvent removedunder vacuum to afford a crude residue containing product (ca. 93%purity). The residue was purified by column chromatography on silica gel(ISCO Combiflash) using CH₂Cl₂/MeOH (1:0 to 9:1) as eluent to give theproduct (473 mg, 73%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.78-7.73 (m, 2H), 7.42-7.38 (m, 2H), 2.49(s, 3H), −1.3 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.2, 137.9, 131.1, 126.6, 120.1, 14.7

m/z=209.27 [M+H]⁺ and 207.41 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₈H₈N₄OS m/z 209.0497, found 209.0482.

Preparation of 1-(3,4,5-trimethoxyphenyl)-1,4-dihydro-5H-tetrazol-5-one6p

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and3,4,5-trimethoxybenzoyl chloride (692 mg, 3.0 mmol) was heated from roomtemperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. overnight(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and the residue partitioned between EtOAc(10 mL) and a saturated aqueous solution of NaHCO₃ (10 mL). The organiclayer was extracted with a further quantity of saturated aqueous NaHCO₃(1×10 mL) [note: organic layer was assessed by TLC to ascertain iftetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (20 mL) was added to the combined NaHCO₃ layers, andthe pH was carefully adjusted to <3 using 6N HCl with efficientstirring. The aqueous and organic layers were partitioned and theaqueous layer was extracted with EtOAc (2×10 mL). The combined organiclayers were dried (Na₂SO₄), filtered and the solvent removed undervacuum to afford a crude residue containing product and carboxylic acidimpurity. The residue was purified by column chromatography on silicagel (ISCO Combiflash) using hexanes/EtOAc (1:0 to 0:1) as eluent to givethe product (155 mg, 20%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.14 (s, 2H), 3.79 (s, 6H), 3.67 (s, 3H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 153.3, 150.3, 136.6, 130.1, 97.6, 60.2,56.1

m/z=253.34 [M+H]⁺ and 251.39 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₁₀H₁₂N₄O₄ m/z 253.0937, found 253.0933.

Preparation of 2-(5-oxo-4,5-dihydro-1H-tetrazol-1yl)phenyl acetate 6q

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and2-chlorocarbonyl)phenyl acetate (566 mg, 3.0 mmol) was heated from roomtemperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. overnight(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and the residue partitioned between EtOAc(10 mL) and a saturated aqueous solution of NaHCO₃ (10 mL). The organiclayer was extracted with a further quantity of saturated aqueous NaHCO₃(1×10 mL) [note: organic layer was assessed by TLC to ascertain iftetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (20 mL) was added to the combined NaHCO₃ layers, andthe pH was carefully adjusted to <3 using 6N HCl with efficientstirring. The aqueous and organic layers were partitioned and theaqueous layer was extracted with EtOAc (2×10 mL). The combined organiclayers were dried (Na₂SO₄), filtered and the solvent removed undervacuum to afford a crude residue containing product and otherimpurities. The residue was purified by column chromatography on silicagel (ISCO Combiflash) using hexanes/EtOAc (1:0 to 0:1) as eluent to givethe product (367 mg, 56%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.66-7.54 (m, 2H), 7.50-7.38 (m, 2H), 2.16(s, 3H), −1.3 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 168.2, 150.5, 144.4, 130.5, 126.9, 126.7,125.4, 124.6, 20.6

m/z=219.45 [M−H]⁺

HRMS (EI): [M−H]⁺ calc'd for C₉H₈N₄O₃ m/z 219.0518, found 219.0507.

Preparation of1-((1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)methyl)-1,4-dihydro-5H-tetrazol-5-one6r

Oxalyl chloride (2.0 M in CH₂Cl₂; 2.3 mL, 4.6 mmol) was added dropwiseover 2-3 min to a stirred suspension of2-(1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetic acid, also knownas Indonmethacin (1.07 g, 3.0 mmol) and DMF (1-2 drops) in CH₂Cl₂ (9 mL)at 0° C. in a vial with pressure-release top. After complete addition,the mixture was allowed to warm to room temperature and stirred at roomtemperature for ca. 60 min. The mixture was concentrated under vacuum toleave the acid chloride 5r, which was used directly in thetetrazolone-forming step below after drying on a high vacuum for 30 min(yield assumed quantitative=1.13 g).

Note: 4.8 mL (12 equiv.) of azidotrimethylsilane used in order to givesufficient volume for acid chloride to dissolve.

A stirred mixture of azidotrimethylsilane (4.8 mL, 18 mmol) and2-(1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetyl chloride (1.13 g,3.0 mmol) was heated from room temperature to 100° C. (blocktemperature) in a sealed vial with pressure-release cap. The temperaturewas lowered to 90° C. and the mixture was stirred at 90° C. overnight(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and then the mixture was dry-loaded on tosilica gel by evaporation from EtOAc. The mixture was purified by columnchromatography on silica gel (ISCO Combiflash) using hexanes/EtOAc (1:0to 0:1) as eluent to the product (0.98 g, 82%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.69-7.60 (m, 4H), 7.21 (d, J=2.4 Hz, 1H),6.89 (d, J=9.0 Hz, 1H), 6.73 (dd, J=9.0, 2.4 Hz, 1H), 5.17 (s, 2H), 3.73(s, 3H), 2.39 (s, 3H), −1.6 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 168.0, 155.6, 151.6, 137.9, 137.2, 133.7,131.3, 130.3, 129.3, 129.1, 114.7, 113.4, 111.6, 101.6, 55.3, 37.1, 13.0

m/z=398.41 [M+H]⁺ and 396.53 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₁₉H₁₆ClN₅O₃ m/z 398.1020, found 398.1034.

HRMS (EI): [M−H]⁺ calc'd for C₁₉H₁₆ClN₅O₃ m/z 396.0863, found 396.0823.

Preparation of4-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-dipropylbenzenesulfonamide 6s

Oxalyl chloride (2.0 M in CH₂Cl₂; 3.0 mL, 6.0 mmol) was added dropwiseover 2-3 min to a stirred suspension of 4-(N,N-dipropylsulfamoyl)benzoicacid (856 mg, 3.0 mmol) and DMF (1-2 drops) in CH₂Cl₂ (6 mL) at 0° C.under nitrogen. After complete addition, the mixture was allowed to warmto room temperature and stirred overnight. The mixture was concentratedunder vacuum to leave the acid chloride 5s, which was used directly inthe tetrazolone-forming step below (yield assumed quantitative=911 mg).

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and4-(N,N-dipropylsulfamoyl)benzoyl chloride (911 mg, 3.0 mmol) was heatedfrom room temperature to 100° C. (block temperature) in a sealed vialwith pressure-release cap. The mixture was then stirred at 100° C.overnight (Note: pressure developed during heating). After cooling, themixture was concentrated under vacuum and the residue partitionedbetween EtOAc (30 mL) and an aqueous saturated NaHCO₃ (30 mL). Theorganic layer was extracted with a further quantity of saturated aqueousNaHCO₃ (8×30 mL) [note: organic layer was assessed by TLC to ascertainif tetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (60 mL) was added to the combined NaHCO₃ layers, andthe pH was carefully adjusted to <3 using 6N HCl with efficientstirring. The aqueous and organic layers were partitioned and theaqueous layer was extracted with EtOAc (2×30 mL). The combined organiclayers were dried (Na₂SO₄), filtered and the solvent removed undervacuum to afford the product (665 mg, 68%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.13-8.08 (m, 2H), 7.98-7.93 (m, 2H), 3.03(t, J=7.7 Hz, 2H), 1.47 (app. sextet, J=7.4 Hz, 2H), 0.79 (t, J=7.4 Hz,3H), −1.1 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.1, 137.8, 137.3, 128.4, 119.0, 49.6,21.6, 11.0

m/z=326.35 [M+H]⁺ and 324.43 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₁₃H₁₉N₅O₃S m/z 326.1287, found 326.1257.

HRMS (EI): [M−H]⁺ calc'd for C₁₃H₁₉N₅O₃S m/z 324.1130, found 324.1116.

Preparation of1-(4′-((1,7-dimethyl-2′-propyl-1H,3′H-[2,5′-dibenzo[d]imidazol]-3′-yl)methyl-[1,1′-biphenyl-2-yl)-1,4-dihydro-5H-tetrazol-5-one6t

Oxalyl chloride (2.0 M in CH₂Cl₂; 0.75 mL, 1.5 mmol) was added dropwiseover 2-3 min to a stirred suspension of4′-((1,7-dimethyl-2′-propyl-1H,3′H-[2,5′-dibenzo[d]imidazol]-3′-yl)methyl-[1,1′-biphenyl)-2-carboxylicacid, also known as Telmisartan (514 mg, 1.0 mmol) and DMF (3 drops) inCH₂Cl₂ (6 mL) at 0° C. under nitrogen. After complete addition, themixture was stirred at 0° C. for 10 min, then allowed to warm to roomtemperature and stirred for 30 min (a yellow then orange solutiondevelops). The mixture was concentrated under vacuum, then fresh CH₂Cl₂(2 mL) was added to the residue and the mixture concentrated undervacuum again to leave the acid chloride 5t, which was used directly inthe tetrazolone-forming step below, after drying on a high vacuum for 15min (yield assumed quantitative=533 mg).

Note: 4.8 mL (36 equiv.) of azidotrimethylsilane used in order to givesufficient volume for the reaction.

A stirred mixture of azidotrimethylsilane (4.8 mL, 36 mmol) and4′-((1,7-dimethyl-2′-propyl-1H,3′H-[2,5′-dibenzo[d]imidazol]-3′-yl)methyl-[1,1′-biphenyl)-2-carbonylchloride (533 mg, 1.0 mmol) was heated from room temperature to 100° C.(block temperature) in a round bottom flask with reflux condenser underan atmosphere of nitrogen. The mixture was then stirred at 100° C. for 2hours. After cooling, the mixture was concentrated under vacuum and MeOHwas added to the residue. The mixture was dry-loaded on to silica geland then purified by column chromatography on silica gel (ISCOCombiflash) using CH₂Cl₂/MeOH (1:0 to 92:8) as eluent to give the pureproduct (87 mg) and mixed fractions. The mixed fractions werere-purified by column chromatography on silica gel (ISCO Combiflash)using CH₂Cl₂/MeOH (1:0 to 92:8) as eluent to give the product (97 mg) asa solid. Total yield of product=184 mg (33%). Also obtained, was afaster-eluting unidentified by-product (181 mg).

¹H NMR (DMSO-d₆, 300 MHz): δ 7.73 (s, 1H), 7.64-7.47 (m, 7H), 7.29-7.11(m, 6H), 5.58 (s, 2H), 3.80 (s, 3H), 2.86 (t, J=7.5 Hz, 2H), 2.61 (s,3H), 1.75 (sextet, J=7.5 Hz, 2H), 0.94 (t, J=7.5 Hz, 3H), −1.5 (br. s,1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 156.2, 154.0, 151.3, 142.6, 142.4, 139.2,136.7, 136.7, 136.6, 134.7, 130.9, 130.7, 130.3, 128.8, 128.6, 128.6,128.3, 126.8, 123.3, 123.2, 122.1, 121.8, 118.6, 110.4, 109.1, 45.9,31.7, 28.7, 20.7, 16.4, 13.8

m/z=555.66 [M+H]⁺ and 553.75 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₃₃H₃₀N₈O m/z 555.2621, found 555.2585.

HRMS (EI): [M−H]⁺ calc'd for C₃₃H₃₀N₈O m/z 553.2465, found 555.2411.

The compound1-(4′-((1,7-dimethyl-2′-propyl-1H,3′H-[2,5′-dibenzo[d]imidazol]-3′-yl)methyl-[1,1′-biphenyl-2-yl)-1,4-dihydro-5H-tetrazol-5-one6t was tested for angiotensin II receptor type 1 (AT 1) antagonistactivity. The inhibition of response to 3 nM angiotensin-II for HEK-293cells expressing hAT1 was assayed. Intracellular [Ca]²⁺ was measured byfluorimetry. The compound1-(4′-((1,7-dimethyl-2′-propyl-1H,3′H-[2,5′-dibenzo[d]imidazol]-3′-yl)methyl-[1,1′-biphenyl-2-yl)-1,4-dihydro-5H-tetrazol-5-one6t had an IC₅₀=1.7 nM (K_(b)=0.14 nM), as shown in FIG. 1A. Forcomparison, Telmisartan had an IC₅₀=5.4 nM (K_(b)=0.44 nM), as shown inFIG. 1B.

Preparation of1-(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)phenyl)-1,4-dihydro-5H-tetrazol-5-one6u

Oxalyl chloride (2.0 M in CH₂Cl₂; 0.38 mL, 0.75 mmol) was added dropwiseover 1 min to a stirred suspension of4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoicacid, also known as Bexarotene (175 mg, 0.5 mmol) and DMF (1-2 drops) inCH₂Cl₂ (5 mL) at 0° C. under nitrogen. After complete addition, themixture was allowed to warm to room temperature and for 2 hr. Themixture was concentrated under vacuum to leave the acid chloride 5u,which was used directly in the tetrazolone-forming step below (yieldassumed quantitative=184 mg).

Note: 1.0 mL (15 equiv.) of azidotrimethylsilane used in order to givesufficient volume for the reaction.

A stirred mixture of azidotrimethylsilane (1.0 mL, 7.5 mmol) and4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoylchloride (184 mg, 0.5 mmol) was heated from room temperature to 100° C.(block temperature) in a 10 mL round-bottom flask under an atmosphere ofnitrogen. The mixture was then stirred at 100° C. for 2 hr, by whichtime LC/MS and TLC analysis indicated completion of the reaction. Aftercooling, CH₂Cl₂ and MeOH was added to the mixture, which was thendry-loaded on to silica gel and purified by column chromatography onsilica gel (ISCO Combiflash) using hexanes/EtOAc (1:0 to 0:1) as eluentto give the product (173 mg, 89%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.82-7.79 (m, 2H), 7.39-7.36 (m, 2H), 7.13(s, 1H), 7.06 (s, 1H), 5.84 (s, 1H), 5.18 (s, 1H), 1.91 (s, 3H), 1.63(br. s, 4H), 1.24 (s, 6H), 1.21 (s, 6H), −1.0 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.2, 147.9, 143.7, 141.8, 138.3, 137.9,133.4, 132.1, 127.9, 127.3, 127.1, 119.5, 115.9, 34.7, 34.6, 33.6, 33.5,31.7, 31.6, 19.5

m/z=389.63 [M+H]⁺ and 387.68 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₂₄H₂₈N₄O m/z 389.2341, found 389.2344.

HRMS (EI): [M−H]⁺ calc'd for C₂₄H₂₈N₄O m/z 387.2185, found 387.2211.

Compound1-(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)phenyl)-1,4-dihydro-5h-tetrazol-5-one6u was tested for agonist activity against retinoid X receptor alpha(RXRα). Activity assays indicated that compound1-(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)phenyl)-1,4-dihydro-5h-tetrazol-5-one6u had an EC₅₀ hRXRα=64 nM. For comparison, Bexarotene had an EC₅₀hRXRα<10 nM, and fluoro-Bexarotene had an EC₅₀ hRXRα=9 nM.

Preparation of 1-(pyridin-3-yl)-1,4-dihydro-5H-tetrazol-5-one 6v

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) andnicotinoyl chloride (425 mg, 3.0 mmol) was heated from room temperatureto 100° C. (block temperature) in a sealed vial with pressure-releasecap. The mixture was then stirred at 100° C. overnight (Note: pressuredeveloped during heating). After cooling, the mixture was concentratedunder vacuum and the residue partitioned between EtOAc (10 mL) and asaturated aqueous solution of NaHCO₃ (10 mL). The organic layer wasextracted with a further quantity of saturated aqueous NaHCO₃ (1×10 mL)[note: organic layer was assessed by TLC to ascertain if tetrazoloneproduct was completely removed. If tetrazolone was still present inorganic layer, then further extractions with saturated NaHCO₃ wereused]. EtOAc (20 mL) was added to the combined NaHCO₃ layers, and the pHwas adjusted to <3 using 6N HCl with efficient stirring. Once acidified,the aqueous layer was re-adjusted to pH 6-7 using saturated NaHCO₃. Theaqueous and organic layers were partitioned and the aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic layers were dried(Na₂SO₄), filtered and the solvent removed under vacuum to afford theproduct (330 mg, 65%) as a solid. A sample was recrystallized fromEtOAc.

¹H NMR (DMSO-d₆, 300 MHz): δ 9.04 (d, J=2.1 Hz, 1H), 8.60 (d, J=4.5 Hz,1H), 8.22 (ddd, J=8.4, 2.7, 1.5 Hz, 1H), 7.58 (dd, J=8.4, 4.8, Hz, 1H),−1.1 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.4, 148.5, 140.7, 131.1, 127.1, 12.2

m/z=162.20 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₆H₅N₅O m/z 164.0572, found 164.0542.

Preparation of 1-(3-chlorothiophen-2-yl)-1,4-dihydro-5H-tetrazol-5-one6w

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and3-chlorothiophene-2-carbonyl chloride (543 mg, 3.0 mmol) was heated fromroom temperature to 100° C. (block temperature) in a sealed vial withpressure-release cap. The mixture was then stirred at 100° C. overnight(Note: pressure developed during heating). After cooling, the mixturewas concentrated under vacuum and the residue partitioned between EtOAc(10 mL) and a saturated aqueous solution of NaHCO₃ (10 mL). The organiclayer was extracted with a further quantity of saturated aqueous NaHCO₃(1×10 mL) [note: organic layer was assessed by TLC to ascertain iftetrazolone product was completely removed. If tetrazolone was stillpresent in organic layer, then further extractions with saturated NaHCO₃were used]. EtOAc (20 mL) was added to the combined NaHCO₃ layers, andthe pH was adjusted to <3 using 6N HCl with efficient stirring. Theaqueous and organic layers were partitioned and the aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic layers were dried(Na₂SO₄), filtered and the solvent removed under vacuum to afford amixture of the desired product and 3-chlorothiophene-2-carboxylic acid.This mixture was purified by column chromatography on silica gel (ISCOCombiflash) using hexanes/EtOAc (1:0 to 0:1) as eluent to give theproduct (185 mg, 30%) as a solid [also obtained from the column was3-chlorothiophene-2-carboxylic acid (20 mg)].

¹H NMR (DMSO-d₆, 300 MHz): δ 7.88 (d, J=6.0 Hz, 1H), 7.25 (d, J=6.0 Hz,1H), −1.1 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 150.5, 128.0, 126.6, 125.8, 123.6

m/z=203.26 [M+H]⁺ and 201.37 [M−H]⁺

HRMS (EI): [M−H]⁺ calc'd for C₅H₃ClN₄OS m/z 200.9638, found 200.9674.

Preparation of1-(3-(2-chlorophenyl)5-methylisoxazol-4-yl)-1,4-dihydro-5H-tetrazol-5-one6x

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) and3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (768 mg, 3.0mmol) was heated from room temperature to 100° C. (block temperature) ina sealed vial with pressure-release cap. The mixture was then stirred at100° C. overnight (Note: pressure developed during heating). Aftercooling, the mixture was concentrated under vacuum and the residuepartitioned between EtOAc (10 mL) and a saturated aqueous solution ofNaHCO₃ (10 mL). The organic layer was extracted with a further quantityof saturated aqueous NaHCO₃ (1×10 mL) [note: organic layer was assessedby TLC to ascertain if tetrazolone product was completely removed. Iftetrazolone was still present in organic layer, then further extractionswith saturated NaHCO₃ were used]. EtOAc (20 mL) was added to thecombined NaHCO₃ layers, and the pH was adjusted to <3 using 6N HCl withefficient stirring. The aqueous and organic layers were partitioned andthe aqueous layer was extracted with EtOAc (2×10 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and the solvent removedunder vacuum to afford the product (713 mg, 86%) as a solid. A samplewas recrystallized from EtOAc.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.58-7.44 (m, 4H), 2.55 (s, 3H), −1.2 (br.s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 167.4, 157.9, 150.8, 132.7, 132.1, 130.3,128.2, 126.2, 115.5, 111.6

m/z=278.36 [M+H]⁺ and 276.51 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₁₁H₈ClN₅O₂ m/z 278.0445, found 278.0450.

Preparation OF methyl (E)-3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)acrylate6y

Oxalyl chloride (2.0 M in CH₂Cl₂; 15.2 mL, 30.3 mmol) was added dropwiseover 2-3 min to a stirred suspension of monomethyl fumarate (2.63 g,20.2 mmol) in CH₂Cl₂ (80 mL) at 0° C. under nitrogen. After completeaddition, the mixture was stirred at 0° C. for 5 min then allowed towarm to room temperature and stirred for 3 hr (a yellow solutiondeveloped). A small aliquot was removed and quenched with MeOH-TLCindicated no acid remaining. The mixture was concentrated under vacuumand CH₂Cl₂ (50 mL) was added to the residue and the mixture concentratedunder vacuum once more to leave the acid chloride 5w, which was useddirectly in the tetrazolone-forming step below (yield assumedquantitative=3.0 g).

Azidotrimethylsilane (16.1 mL, 121.2 mmol) was added in one portion tothe acid chloride from the above procedure (3.0 g, 20.2 mmol) at roomtemperature (gas evolution was noted). The mixture was place undernitrogen and heated from room temperature to 100° C. (blocktemperature), then stirred at 100° C. for 90 min. After cooling to roomtemperature, the excess solvent was removed under vacuum to leave acrude residue. EtOAC (150 mL) and saturated NaHCO₃ (150 mL) were addedto the residue. A solid was noticed, so the mixture was filtered. Thefilter cake was dissolved in H₂O (350 mL) and then combined with thesaturated NaHCO₃ layer of the filtrate. EtOAc (150 mL) was added to thecombined aqueous system described above, and the mixture was acidifiedto ca. pH 3 with 1N HCl. The aqueous and organic layers were partitionedand the aqueous layer was extracted with EtOAc (2×100 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered and the solvent removedunder vacuum to leave a crude residue (2.6 g; ca. 90% purity of desiredproduct). The residue was purified by column chromatography on silicagel using CH₂Cl₂/MeOH (1:0 to 9:1) as eluent to give the product (2.14g, 62% over 2 steps) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 7.73 (d, J=14.4 Hz, 1H), 6.49 (d, J=14.4Hz, 1H), 3.71 (s, 3H), −1.0 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 165.7, 149.8, 132.3, 106.3, 51.9

m/z=169.34 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₅H₆N₄O₃ m/z 171.0518, found 171.0522.

Preparation of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one 6z

A stirred mixture of azidotrimethylsilane (2.4 mL, 18 mmol) andpropionyl chloride (278 mg, 3.0 mmol) was heated from room temperatureto 100° C. (block temperature) in a sealed vial with pressure-releasecap. The mixture was then stirred at 100° C. overnight (Note: pressuredeveloped during heating). After cooling, the mixture was concentratedunder vacuum and the residue partitioned between EtOAc (10 mL) and asaturated aqueous solution of NaHCO₃ (10 mL). The organic layer wasextracted with a further quantity of saturated aqueous NaHCO₃ (1×10 mL)[note: organic layer was assessed by TLC to ascertain if tetrazoloneproduct was completely removed. If tetrazolone was still present inorganic layer, then further extractions with saturated NaHCO₃ wereused]. EtOAc (20 mL) was added to the combined NaHCO₃ layers, and the pHwas adjusted to <3 using 6N HCl with efficient stirring. The aqueous andorganic layers were partitioned and the aqueous layer was extracted withEtOAc (2×10 mL). The combined organic layers were dried (Na₂SO₄),filtered and the solvent removed under vacuum to afford the product (49mg, 14%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 3.86 (q, J=7.3 Hz, 2H), 1.26 (t, J=7.3 Hz,3H), −1.7 (br. s, 1H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 151.6, 38.7, 13.7

Example 2

Reactions were performed to form tetrazolone derivatives of activeagents having a carboxyl group, where a tetrazolone group served as abioisostere of the carboxyl group.

Preparation of(Z)-1-(3′-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazinyl)-2′-hydroxy-[1,1′-biphenyl]-3-yl)-1,4-dihydro-5H-tetrazol-5-one

Diphenyl phosphoryl azide (196 μL, 0.9 mmol) was added to a stirredsolution of Eltrombopag (365 mg, 0.83 mmol) and Et₃N (140 μL, 1.0 mmol)in CH₂Cl₂ (10 mL) at 0° C. under an atmosphere of nitrogen. The mixturewas stirred at 0° C. for 2 min, then allowed to warm to room temperatureand stirred for 2 hr. Further aliquots of diphenyl phosphoryl azide (196μL, 0.9 mmol) and Et₃N (140 μL, 1.0 mmol) were added and the mixture wasstirred at room temperature overnight. H₂O (15 mL) and CH₂Cl₂ (10 mL)were added and the aqueous and organic layers were partitioned. Theaqueous layer was extracted with CH₂Cl₂ (1×20 mL), and the combinedorganic layers were dried over Na₂SO₄, filtered and the solvent removedunder vacuum to leave a crude solid.

The solid was suspended in azidotrimethylsilane (10 mL), placed under anitrogen atmosphere and then slowly heated from room temperature to 100°C. The mixture was stirred at 100° C. for 10 min. As the mixture wasstill a suspension, it was removed from the heat and allowed to cool.1,4-Dioxane (10 mL) was added and the mixture was returned to the heatblock and a solution formed. The mixture was stirred at 100° C. undernitrogen for 6 hr. The solvent was removed under vacuum [note: at thisstage LC/MS indicated that the phenol had been protected as a TMSether]. The mixture was suspended in THF (10 mL) and a 1N solution oftetrabutylammonium fluoride in THF (1 mL) was added, and the mixture wasstirred at room temperature for 1 hr. The mixture was dry-loaded on tosilica gel and was purified by column chromatography on silica gel usingDCM/(MeOH/AcOH) as eluent. While collecting fractions, some solidproduct had precipitated in some fractions. The main fractions werefiltered and the filter cake was washed with MeOH to afford the desiredproduct (155 mg, 40%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 13.72 (br. s, 1H), 9.72 (br. s, 1H), 8.06(s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.72-7.58 (m, 5H), 7.19-7.10 (m, 3H),2.20 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), −1.18 (br. s, 1H)

m/z=483.22 [M+H]⁺ and 481.26 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₂₅H₂₂N₈O₃ m/z 483.1868, found 481.1893.

HRMS (EI): [M−H]⁺ calc'd for C₂₅H₂₂N₈O₃ m/z 481.1741, found 481.1737.

Preparation of9-methyl-3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

Oxalyl chloride (2.0 M in CH₂Cl₂; 1.0 mL, 2.0 mmol) was added to astirred suspension of Pemirolast (204 mg, 1.0 mmol) in CH₂Cl₂ (5 mL) at0° C. under an atmosphere of nitrogen. The mixture was allowed to warmto room temperature and stirred overnight. An analytical sample wasremoved and quenched with MeOH. Analysis of the sample by LC/MSindicated a complete reaction. The mixture was concentrated under vacuumto leave a crude residue.

The residue was suspended in 1,4-dioxane (5 mL) and azidotrimethylsilane(5 mL) and placed under an atmosphere of nitrogen. The mixture was thenslowly heated from room temperature to 100° C. and stirred at 100° C.for 4 hr. The mixture was cooled, and dry-loaded on to silica gel.Purification by silica gel chromatography using CH₂Cl₂/MeOH (1:0 to 9:1)as eluent gave the desired product (41 mg, 18%) as a solid [note: mixedfractions containing product were not isolated].

¹H NMR (DMSO-d₆, 300 MHz): δ 8.94 (dd, J=7.1, 0.6 Hz, 1H), 8.68 (d,J=0.6 Hz, 1H), 8.02 (d, J=7.1 Hz, 1H), 7.45 (app. t, J=7.1 Hz, 1H), 2.56(s, 3H), −1.32 (br. s, 1H)

m/z=245.10 [M+H]⁺ and 243.18 [M−H]

HRMS (EI): [M+H]⁺ calc'd for C₁₀H₈N₆O₂ m/z 245.0776, found 245.0787.

HRMS (EI): [M−H]⁺ calc'd for C₁₀H₈N₆O₂ m/z 243.0634, found 243.0630.

Preparation of(S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-6-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one

Diphenyl phosphoryl azide (323 μL, 1.5 mmol) was added to a stirredsolution of Levofloxacin (361 mg, 1.0 mmol) and Et₃N (280 μL, 2.0 mmol)in CH₂Cl₂ (10 mL) at 0° C. under an atmosphere of nitrogen. The mixturewas stirred at 0° C. for 15 min, then allowed to warm to roomtemperature and stirred for 4 hr. Further aliquots of diphenylphosphoryl azide (323 μL, 1.0 mmol) and Et₃N (280 μL, 2.0 mmol) wereadded and the mixture was stirred at room temperature overnight. H₂O (20mL) and CH₂Cl₂ (15 mL) were added and the aqueous and organic layerswere partitioned. The aqueous layer was extracted with CH₂Cl₂ (2×20 mL),and the combined organic layers were dried over Na₂SO₄, filtered and thesolvent was removed under vacuum to leave a crude residue.

The residue was suspended in azidotrimethylsilane (5 mL) and 1,4-dioxane(5 mL), then placed under an atmosphere of nitrogen. The mixture wasslowly heated from room temperature to 100° C., and then stirred at 100°C. for 4 hr. After cooling, the mixture was dry-loaded on to silica geland purified by column chromatography on silica gel usingCHCl₃/(MeOH/NH₄OH; 7:1) [1:0 to 7:3] as eluent to give the product as asolid.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.51 (s, 1H), 7.39 (d, J=12.3 Hz, 1H),4.62-4.54 (m, 1H), 4.47 (dd, J=11.4, 1.5 Hz, 1H), 4.34 (dd, J=11.4, 2.1Hz, 1H), 3.25 (br. s, 8H), 2.24 (s, 3H), 1.41 (d, J=6.3 Hz, 3H)

¹⁹F NMR (DMSO-d₆, 282 MHz): δ −122.9 (d, J=12.3 Hz)

m/z=402.91 [M+H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₁₀H₈N₆O₂ m/z 402.1701, found 402.1690.

HRMS (EI): [M−H]⁺ calc'd for C₁₀H₈N₆O₂ m/z 400.1527, found 400.1534.

Preparation of4-hydroxy-1-methyl-N-((5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-7-phenoxyisoquinoline-3-carboxamide

Diphenyl phosphoryl azide (216 μL, 1.0 mmol) was added to a stirredsolution of FG4592 (177 mg, 0.5 mmol) and Et₃N (210 μL, 1.5 mmol) inCH₂Cl₂ (5 mL) at 0° C. under an atmosphere of nitrogen. The mixture wasstirred at 0° C. for 15 min, then allowed to warm to room temperatureand stirred at room temperature overnight. H₂O (20 mL) and CH₂Cl₂ (15mL) were added and the aqueous and organic layers were partitioned. Theaqueous layer was extracted with CH₂Cl₂ (1×20 mL), and the combinedorganic layers were dried over Na₂SO₄, filtered and the solvent wasremoved under vacuum to leave a crude residue.

The residue was suspended in azidotrimethylsilane (5 mL) and 1,4-dioxane(5 mL), then placed under an atmosphere of nitrogen. The mixture wasslowly heated from room temperature to 100° C., and then stirred at 100°C. overnight. After cooling, the mixture was dry-loaded on to silica geland purified by column chromatography on silica gel to give the product(85 mg, 43%) as a solid.

¹H NMR (DMSO-d₆, 300 MHz): δ 13.19 (s, 1H), 9.20 (t, J=6.3 Hz, 1H), 8.68(t, J=5.7 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H),7.54-7.43 (m, 3H), 7.24 (tt, J=7.5, 1.2 Hz, 1H), 7.18-7.14 (m, 2H), 4.72(t, J=6.0 Hz, 2H), 2.67 (s, 3H)

¹³C NMR (DMSO-d₆, 75 MHz): δ 169.8, 157.9, 156.1, 155.5, 153.1, 147.0,131.5, 130.4, 125.3, 124.6, 123.4, 122.5, 119.5, 119.2, 112.1, 45.2,21.4

m/z=393.17 [M+H]⁺& 391.20 [M−H]⁺

HRMS (EI): [M+H]⁺ calc'd for C₁₉H₁₆N₆O₄ m/z 393.1311, found 393.1327.

HRMS (EI): [M−H]⁺ calc'd for C₁₉H₁₆N₆O₄ m/z 391.1529, found 391.1155.

Preparation OF(E)-4-(2-(4-oxo-3-(3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)-3,4-dihydroquinazolin-2-yl)vinyl)benzonitrile

Preparation of 1-(3-aminophenyl)-1,4-dihydro-5H-tetrazol-5-one

A mixture of 1-(3-nitrophenyl)-1,4-dihydro-5H-tetrazol-5-one (130 mg,0.63 mmol) and palladium on charcoal (Aldrich Cat. No. 330108; 13 mg) inMeOH (10 mL) was hydrogenated at 20 psi for 3 hr. The mixture was thenfiltered through celite and the filter cake washed with MeOH (×3). Thefiltrate was concentrated under vacuum to leave the product, which wasused directly in the next step (yield assumed quantitative=111 mg).

rt=1.43 min; m/z=178.11 [M+H]⁺& 176.16 [M−H]⁺

Preparation of2-methyl-3-(3-(5-oxo-4,5-dihydro-1H-tetrazol-yl)phenyl)quinazolin-4(3H)-one

A mixture of 2-methyl-4H-benzo[d][1,3]oxazin-4-one (101 mg, 0.63 mmol)and 1-(3-aminophenyl)-1,4-dihydro-5H-tetrazol-5-one (111 mg, 0.63 mmol)in AcOH (10 mL) was heated to reflux and stirred overnight. Analysisindicated the formation of product. The mixture was allowed to cool anddry-loaded onto silica gel. The mixture was purified by columnchromatography on silica gel using CH₂Cl₂/MeOH (1:0 to 9:1) as eluent togive the product (32 mg, 16% ca. 94% purity by LC/MS). The product wasused directly in the next step.

rt=3.88 min; m/z=321.15 [M+H]⁺& 319.23 [M−H]⁺

Preparation of(E)-4-(2-(4-oxo-3-(3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)-3,4-dihydroquinazolin-2-yl)vinyl)benzonitrile

A mixture of2-methyl-3-(3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)quinazolin-4(3H)-one(32 mg, 0.1 mmol) and 4-cyanobenzaldehyde (16 mg, 0.12 mmol) in AcOH (5mL) was heated to reflux and stirred for 3 days (continuously monitoredby LC/MS, which indicated product formation after 3 hr). After cooling,the mixture was dry-loaded onto silica gel and purified by columnchromatography on silica gel using CH₂Cl₂/MeOH (1:0 to 95:5) as eluentto give a solid (11 mg; desired product ca. 70% purity). The solid wasre-purified by preparative thin-layer chromatography using CH₂Cl₂/MeOH(9:1) as eluent to give the product (6 mg, 14%) as a solid.

rt=5.95 min; m/z=434.19 [M+H]⁺& 432.23 [M−H]⁺

¹H NMR (CD OD; 300 MHz): δ 8.15-8.09 (m, 2H), 8.01 (t, J=2.0 Hz, 1H),7.83 (d, J=15.5 Hz, 1H), 7.82-7.71 (m, 2H), 7.64 (t. J=8.0 Hz, 1H), 7.55(d, J=8.7 Hz, 2H), 7.49-7.42 (m, 3H), 7.24 (ddd, J=7.8, 2.7, 0.9 Hz,1H), 6.54 (d, J=15.5 Hz, 1H)

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound comprising a tetrazolone derivative of a carboxyl group of an active agent.
 2. The compound of claim 1, wherein the tetrazolone derivative comprises a tetrazolone or a substituted tetrazolone.
 3. The compound of claim 1, wherein the compound is of the formula:

wherein R¹ is the active agent; and R² is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl; or a salt or stereoisomer thereof.
 4. The compound of claim 3, wherein R² is hydrogen or alkyl.
 5. The compound of claim 1, wherein the active agent is a therapeutically effective active agent.
 6. The compound of claim 1, wherein the tetrazolone derivative is produced from the carboxyl group of the active agent.
 7. The compound of claim 1, wherein the compound is selected from:


8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 9. The pharmaceutical composition of claim 8, further comprising a second active agent.
 10. A compound comprising a tetrazolone or substituted tetrazolone produced from a carboxyl group of an active agent.
 11. A method of treating a disease or disorder in a subject in need of treatment, the method comprising administering to the subject a compound comprising a tetrazolone derivative of a carboxyl group of an active agent.
 12. The method of claim 11, wherein the tetrazolone derivative comprises a tetrazolone or a substituted tetrazolone.
 13. The method of claim 11, wherein the compound is of the formula:

wherein R¹ is the active agent; and R² is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a salt or stereoisomer thereof.
 14. The method of claim 13, wherein R² is hydrogen or alkyl.
 15. The method of claim 11, wherein the active agent is a therapeutically effective active agent.
 16. The method of claim 11, wherein the tetrazolone derivative is produced from the carboxyl group of the active agent.
 17. The method of claim 11, wherein the compound is selected from: 